Search CTL/CD8+ T-Cell Epitope Database

Found 90 matching records:

Displaying record number 57521

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(A*0201)
Immunogen	in vitro stimulation or selection
Experimental methods	Tetramer binding
Keywords

Notes

The study investigated the effect of blocking interleukin-10 (IL-10) on HIV-specific CTL responses. PBMCs from viremic and aviremic patients were stimulated with optimal HIV epitopes in the presence of IL-10 receptor antibody. Blocking the receptor increased the number of HIV-specific CTLs, and the effect was higher in viremic than in aviremic patients.
This epitope was one of 12 known optimal epitopes used to stimulate PBMC from viremic and aviremic patients in order to test the effect of blocking IL-10.

References

Brockman2009 Mark A. Brockman, Douglas S. Kwon, Daniel P. Tighe, David F. Pavlik, Pamela C. Rosato, Jennifer Sela, Filippos Porichis, Sylvie Le Gall, Michael T. Waring, Kristin Moss, Heiko Jessen, Florencia Pereyra, Daniel G. Kavanagh, Bruce D. Walker, and Daniel E. Kaufmann. IL-10 Is Up-Regulated in Multiple Cell Types During Viremic HIV Infection and Reversibly Inhibits Virus-Specific T Cells. Blood, 114(2):346-356, 9 Jul 2009. PubMed ID: 19365081. Show all entries for this paper.

Displaying record number 53722

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	BRU
Subtype	B, CRF02_AG
Species (MHC/HLA)	human(A2, B8)
Immunogen	HIV-1 infection
Country	Cote D'Ivoire
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	subtype comparisons

Notes

CD8+ T-cells from HIV-1 CRF02_AG-infected Ivorians could recognize clade B epitopes. No difference was observed in the number of recognized peptide pools between nine French subtype B infected study subjects, and nine CRF02_AG infected Ivorian subjects.
This epitope was recognized by 1/9 CRF02_AG-infected Ivorians, and 2/9 B-infected French subjects.

References

Inwoley2005 André Inwoley, Patricia Recordon-Pinson, Marion Dupuis, Jessintha Gaston, Mathieu Genête, Albert Minga, Franck Letourneur, François Rouet, Jeannine Choppin, Hervé Fleury, Jean-Gérard Guillet, Muriel Andrieu, and ANRS 1220 PRIMO-CI Study Group. Cross-Clade Conservation of HIV Type 1 Nef Immunodominant Regions Recognized by CD8+ T Cells of HIV Type 1 CRF02\_AG-Infected Ivorian (West Africa). AIDS Res. Hum. Retroviruses, 21(7):620-628, Jul 2005. PubMed ID: 16060833. Show all entries for this paper.

Displaying record number 1838

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(A3)
Immunogen	HIV-1 infection
Experimental methods
Keywords	dendritic cells

Notes

The role of CD4+ T-cell help in expansion of virus-specific memory CTL was studied through co-culture ex vivo
Optimal expansion of HIV-1-specific memory CTL depended on CD4+ T cell help in 9 of 10 patients -- CD40 ligand trimer (CD40LT) could enhance CTL in the absence of CD4+ T cell help to a variable degree in most of patients.
Those CTL that didn't respond to CD40LT could expand with IL2 present, and IL15 produced by dendritic cells also contributes.
The T-helper epitope used for CD4+ T cell stimulation was the universal tetanus helper epitope TET830-843 (QYIKANSKFIGITE)

References

Ostrowski2000 M. A. Ostrowski, S. J. Justement, L. Ehler, S. B. Mizell, S. Lui, J. Mican, B. D. Walker, E. K. Thomas, R. Seder, and A. S. Fauci. The role of CD4+ T cell help and CD40 ligand in the in vitro expansion of HIV-1-specific memory cytotoxic CD8+ T cell responses. J. Immunol., 165(11):6133-41, 1 Dec 2000. URL: http://www.jimmunol.org/cgi/content/full/165/11/6133. PubMed ID: 11086046. Show all entries for this paper.

Displaying record number 59667

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B*07)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	rate of progression, optimal epitope

Notes

Correlation between HLA class I and spontaneous control of HIV-1 was significant for 7-8 epitopes when 341 chronic, HIV-infected subjects, divided into controllers and non-controllers, were tested for EliSpot responses to 257 optimally defined epitopes. 21 epitopes were associated with viral progression. Protective epitopes tend to cluster in regions of critical stability for the protein, therefore constraining escape.
FLKEKGGL had a significantly positive association with HLA B*07; it was recognized by 9/27 B*07-positive subjects and 12/190 B*07-negative subjects.

References

Pereyra2014 Florencia Pereyra, David Heckerman, Jonathan M. Carlson, Carl Kadie, Damien Z. Soghoian, Daniel Karel, Ariel Goldenthal, Oliver B. Davis, Charles E. DeZiel, Tienho Lin, Jian Peng, Alicja Piechocka, Mary Carrington, and Bruce D. Walker. HIV Control Is Mediated in Part by CD8+ T-Cell Targeting of Specific Epitopes. J. Virol., 88(22):12937-12948, Nov 2014. PubMed ID: 25165115. Show all entries for this paper.

Displaying record number 62128

HXB2 Location	Nef(90-97)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	B*08-FL8
Species (MHC/HLA)	human(B*08)
Immunogen	computer prediction
Country	Argentina
Experimental methods	Other, Relative replication capacity assay
Keywords	binding affinity, structure, assay or method development, contact residues

Notes

Genome-wide association studies (GWAS) are used in a novel method of predicting residues in conserved epitopes with a high mutation cost to HIV fitness that are best targeted by a vaccine. Protein structure-based network analysis was used to quantify the topological importance of each residue to the tertiary and quaternary structure of HIV p24 protein as residue-residue interactions. A network score was generated for each residue (node) using data on non-covalent interactions (edges) - van der Waals interactions, hydrogen bonds, salt bridges, disulfide bonds, π-π interactions, π-cation interactions, metal-coordinated bonds and local hydrophobic packing. Residues of low-mutation tolerance were at important network positions and impaired viral replication fitness greatly. These residues were found in highly networked epitopes that were presented more often by protective HLA. Natural controllers of infection targeted more of these highly networked CTL epitopes, even in the absence of protective presenting HLA alleles.
Comparison within 5,430 Clade B isolates showed an inverse relationship between network score and mutational frequency in 11 additional HIV proteins. Gag p24 was the most highly networked protein due to extensive capsid multimerization requirements, making it mutationally fragile and linking Gag-specific CTL breadth with lower VL.
Experimental mutation of highly networked residues resulted in impairment of HIV infectivity at 2 days and viral replication at 7 days but mutation of residues with poor network scores was not impactful.
Risk versus Protective HLA alleles were able to be delineated by averaging residue network scores involved in HLA binding, TCR recognition, and peptide processing of an epitope associated with that HLA allele. Protective vs. non-protective HLA of controllers, however, had no significant difference in their eptiopes' network scores.
Neutral-HLA-restricted immunodominant epitopes of controller subjects contained much more highly networked residues than progressor subjects'. Controllers and progressors with similar CTL proliferation also had a significant difference in the sum of network scores of targeted epitopes.
FL8 is the representative epitope of a low network score with a robust proliferative CTL response. FL8 binds HLA-B*0801, and has a normalized network score of 1.75. Numerous mutations were detected in this epitope (as opposed to similar high network scoring epitopes), which abrogated later CTL recognition. K92 and K94 were HLA anchors while L91, E93, G95 and G96 make TCR contacts.
Supplementary Table S3 contains Epitope Network Scores of 260 HIV optimal CTL epitopes, pp. 25-27, http://science.sciencemag.org/content/suppl/2019/05/01/364.6439.480.DC1.

References

Gaiha2019 Gaurav D. Gaiha, Elizabeth J. Rossin, Jonathan Urbach, Christian Landeros, David R. Collins, Chioma Nwonu, Itai Muzhingi, Melis N. Anahtar, Olivia M. Waring, Alicja Piechocka-Trocha, Michael Waring, Daniel P. Worrall, Musie S. Ghebremichael, Ruchi M. Newman, Karen A. Power, Todd M. Allen, James Chodosh, and Bruce D. Walker. Structural Topology Defines Protective CD8+ T Cell Epitopes in the HIV Proteome. Science, 364(6439):480-484, 3 May 2019. PubMed ID: 31048489. Show all entries for this paper.

Displaying record number 1015

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(89-97 LAI)
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Patient MHC/HLA	A1, B7, B8, Cw0701, Cw0702
Experimental methods	Chromium-release assay, HLA binding
Keywords	review, escape

Notes

CTL escape variants appeared over time in HLA-B*08 HIV-1+ individual, providing evidence of immune escape.
Most variants appear at position 5, an anchor residue.
FLKE(e,n or q)GGL and FL(d)KGGL showed reduced binding efficiency and recognition.
Double mutants (FiKEnGGL, FLeEnGGL, and FLKgnGGL) completely escaped recognition.
Other mutants were sLKEKGGL, lLKEKGGL, which were recognized strongly by CTL.
Deletions of the epitope were also seen in some proviral clones.
Goulder1997e is a review of immune escape that summarizes this study in the context of CTL escape to fixation.

References

Goulder1997e P. Goulder, D. Price, M. Nowak, S. Rowland-Jones, R. Phillips, and A. McMichael. Co-Evolution of Human Immunodeficiency Virus and Cytotoxic T-Lymphocyte Responses. Immunol. Rev., 159:17-29, 1997. PubMed ID: 9416500. Show all entries for this paper.

Price1997 D. A. Price, P. J. Goulder, P. Klenerman, A. K. Sewell, P. J. Easterbrook, M. Troop, C. R. Bangham, and R. E. Phillips. Positive Selection of HIV-1 Cytotoxic T Lymphocyte Escape Variants during Primary Infection. Proc. Natl. Acad. Sci. U.S.A., 94:1890-1895, 1997. Cytotoxic T lymphocytes (CTLs) are thought to play a crucial role in the termination of the acute primary HIV-1 syndrome, but clear evidence for this presumption has been lacking. Here we demonstrate positive selection of HIV-1 proviral sequences encoding variants within a CTL epitope in Nef, a gene product critical for viral pathogenicity, during and after seroconversion. These positively selected HIV-1 variants carried epitope sequence changes that either diminished or escaped CTL recognition. Other proviruses had mutations that abolished the Nef epitope altogether. These results provide clear evidence that CTLs exert selection pressure on the viral population in acute HIV-1 infection. PubMed ID: 9050875. Show all entries for this paper.

Displaying record number 1800

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Experimental methods
Keywords

Notes

B*08-restricted CTL accounted for about 1/3 of the total CTL response in one individual.
The response to FLKEKGGL was the second highest response in magnitude compared to all the HLA class I A- and B-restricted epitopes tested in this individual.

References

Day2001 C. L. Day, A. K. Shea, M. A. Altfeld, D. P. Olson, S. P. Buchbinder, F. M. Hecht, E. S. Rosenberg, B. D. Walker, and S. A. Kalams. Relative dominance of epitope-specific cytotoxic T-lymphocyte responses in human immunodeficiency virus type 1-infected persons with shared HLA alleles. J. Virol., 75(14):6279-91, Jul 2001. URL: http://jvi.asm.org/cgi/content/full/75/14/6279. PubMed ID: 11413294. Show all entries for this paper.

Displaying record number 1993

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	Nef-FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	HAART, ART

Notes

Among HIV+ individuals who carried HLA B*08, 1/3 (33%) recognized this epitope.

References

Sabbaj2003 Steffanie Sabbaj, Anju Bansal, G. Douglas Ritter, Christopher Perkins, Bradley H. Edwards, Ethan Gough, Jianming Tang, James J. Szinger, Bette Korber, Craig M. Wilson, Richard A. Kaslow, Mark J. Mulligan, and Paul A. Goepfert. Cross-Reactive CD8+ T Cell Epitopes Identified in US Adolescent Minorities. J. Acquir. Immune Defic. Syndr., 33(4):426-438, 1 Aug 2003. PubMed ID: 12869831. Show all entries for this paper.

Displaying record number 55086

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef( SF2)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ, Intracellular cytokine staining, Tetramer binding
Keywords	TCR usage

References

Meyer-Olson2006 Dirk Meyer-Olson, Kristen W. Brady, Melissa T. Bartman, Kristin M. O'Sullivan, Brenna C. Simons, Joseph A. Conrad, Coley B. Duncan, Shelly Lorey, Atif Siddique, Rika Draenert, Marylyn Addo, Marcus Altfeld, Eric Rosenberg, Todd M. Allen, Bruce D. Walker, and Spyros A. Kalams. Fluctuations of Functionally Distinct CD8+ T-Cell Clonotypes Demonstrate Flexibility of the HIV-Specific TCR Repertoire. Blood, 107(6):2373-2383, 15 Mar 2006. PubMed ID: 16322475. Show all entries for this paper.

Displaying record number 55277

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	characterizing CD8+ T cells

Notes

Maturation phenotypes of CTLs were compared between HIV-1 Controller and Progressor subjects. Controllers were found to recognize a median of 18 epitopes compared to 15 by Progressors. While Controllers certainly had higher frequencies of terminally differentiated effector CTLs (CD45RA+/CCR7-), Progressors had higher mean frequencies of CD45RA-/CCR7- effector memory, CD45RA-/CCR7+ central memory (statistically significant) and CD45RA+/CCR7+ naive CTLs. No correlation was seen between CTL effector phenotype and either HLA-type or epitope.
B*08-restricted epitope FLKEKGGL does not correlate with any particular CTL maturation phenotype.

References

Addo2007 Marylyn M. Addo, Rika Draenert, Almas Rathod, Cori L. Verrill, Benjamin T. Davis, Rajesh T. Gandhi, Gregory K. Robbins, Nesli O. Basgoz, David R. Stone, Daniel E. Cohen, Mary N. Johnston, Theresa Flynn, Alysse G. Wurcel, Eric S. Rosenberg, Marcus Altfeld, and Bruce D. Walker. Fully Differentiated HIV-1 Specific CD8+ T Effector Cells Are More Frequently Detectable in Controlled than in Progressive HIV-1 Infection. PLoS ONE, 2(3):e321, 2007. PubMed ID: 17389912. Show all entries for this paper.

Displaying record number 55333

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(89-96)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ, Intracellular cytokine staining
Keywords	rate of progression, acute/early infection, memory cells

Notes

CD127 hi memory CTLs were correlated with different patient groups - subjects with chronic HIV-1 infection or controllers or those treated early with ART. For patients with chronic infection, CD127 hi CTL levels decrease greatly. Early ART treatment alone maintained these long-lived memory T cells.
In response to epitope FL8, FLKEKGGL, IFN-gamma and TNF-alpha were produced by CD127 lo cells in chronic patients with viremia. IL-2 was produced by both CD127 hi and lo cells. HLA-restriction was to -B*8.

References

Sabbaj2007 Steffanie Sabbaj, Sonya L. Heath, Anju Bansal, Sameera Vohra, J Michael Kilby, Allan J. Zajac, and Paul A. Goepfert. Functionally Competent Antigen-Specific CD127(hi) Memory CD8+ T Cells Are Preserved Only in HIV-Infected Individuals Receiving Early Treatment. J. Infect. Dis., 195(1):108-117, 1 Jan 2007. PubMed ID: 17152014. Show all entries for this paper.

Displaying record number 55750

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Patient MHC/HLA	A1, A2, B49, B8, Cw7
Country	Germany
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	escape, mutation acquisition

Notes

The Nef HLA-B8-restricted dominant epitope FL8, FLKEKGGL, was studied both longitudinally over time as well as horizontally in a 56 subject cohort of HIV-1 infected patients to chart FL8 variants and . FL8 mutants were associated with higher pVL and lower CD4 cell counts.
Mutations in FL8 seen in B8-positive patients were FLKEqGGL, FLKEnGGL, FLKEmGGL, FLKEtGGL, FLKEeGGL, FLrEKGGL, FLrdKGGL and FLrkeGGL.
Mutations in FL8 seen in B8-negative patients were FLrEKGGL, FLrkeGGL, FLrkKGGL, FLqEqGGL, FLiaKGGL and lLKEKGGL.
HLA restrictions in this study are previously published and correlate with the subject's HLA. All variants except for FL8-V2 (FLrdKGGL) were recognized though to a lower degree than wild type FL8, by Patient 01.

References

Maurer2008 Katja Maurer, Ellen G. Harrer, Andreas Goldwich, Kathrin Eismann, Silke Bergmann, Matthias Schmitt-Haendle, Bernd Spriewald, Sandra M. Mueller, Thomas Harrer, and German Competence Network for HIV/AIDS. Role of Cytotoxic T-Lymphocyte-Mediated Immune Selection in a Dominant Human Leukocyte Antigen-B8-Restricted Cytotoxic T-Lymphocyte Epitope in Nef. J. Acquir. Immune Defic. Syndr., 48(2):133-141, 1 Jun 2008. PubMed ID: 18391752. Show all entries for this paper.

Displaying record number 56407

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	Australia, Canada, Germany, United States
Experimental methods
Keywords	escape, HLA associated polymorphism

Notes

98 newly infected patients were studied to track early host HLA and Gag/Pol/Nef epitope immune responses' association with viral evolution. Response hierarchies were the same as those for later infection, and 50% of the most rapidly substituting epitopes were restricted by protective HLA, e.g. Gag B*57-associated mutations which were the most rapidly reverting upon transmission to a non-B*57-host. While there are great differences in mutation rates and reversions across the HIV proteome, most early viral change is driven by immune pressure.
HLA-driven epitope evolution was seen in 80% of published CTL epitopes.
HLA-B*08-associated substitutions within optimally defined epitope FLKEKGGL are at positions L2, E4 and K5, FlKekGGL. FL8 has a high (>70%) recognition frequency and robust escape rate.

References

Brumme2008 Zabrina L. Brumme, Chanson J. Brumme, Jonathan Carlson, Hendrik Streeck, Mina John, Quentin Eichbaum, Brian L Block, Brett Baker, Carl Kadie, Martin Markowitz, Heiko Jessen, Anthony D. Kelleher, Eric Rosenberg, John Kaldor, Yuko Yuki, Mary Carrington, Todd M. Allen, Simon Mallal, Marcus Altfeld, David Heckerman, and Bruce D. Walker. Marked Epitope- and Allele-Specific Differences in Rates of Mutation in Human Immunodeficiency Type 1 (HIV-1) Gag, Pol, and Nef Cytotoxic T-Lymphocyte Epitopes in Acute/Early HIV-1 Infection. J. Virol., 82(18):9216-9227, Sep 2008. PubMed ID: 18614631. Show all entries for this paper.

Displaying record number 56757

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	United Kingdom
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	acute/early infection

Notes

The study analyzed the kinetics of the HIV-specific CD8+ T-cell response in 21 acutely infected subjects. The first responses peaked at as early as 5 days, but were of limited epitope breadth. Responses of additional specificities expanded in subsequent waves, resulting in successive shifts in epitope immunodominance over time. The results document the preferential expansion of CD8+ T cells recognizing a subset of epitopes in acute infection and suggest that the initial T-cell response may influence the efficiency of viral containment in early infection.
FLKEKGGL is an optimally-defined epitope targeted by the first-analyzed T-cell responses in acute infection.

References

Turnbull2009 Emma L. Turnbull, MaiLee Wong, Shuyi Wang, Xiping Wei, Nicola A. Jones, Karen E. Conrod, Diana Aldam, Jo Turner, Pierre Pellegrino, Brandon F. Keele, Ian Williams, George M. Shaw, and Persephone Borrow. Kinetics of Expansion of Epitope-Specific T Cell Responses During primary HIV-1 Infection. J. Immunol., 182(11):7131-7145, 1 Jun 2009. PubMed ID: 19454710. Show all entries for this paper.

Displaying record number 57578

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	(B*08)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	acute/early infection

Notes

Responses to specific B57/58, B27, and B35-restricted epitopes were tested in a cohort of 45 subjects during primary infection. The presence of certain B57/58, B27, and B35-restricted T-cell responses during primary infection better defined disease progression than the HLA genotype alone, suggesting that it is the HIV-specific CD8+ T-cells and not the presence of a particular HLA allele, that determine disease progression.
3/7 B08-positive subjects responded to FLKEKGGL, and 21% of the patients' total response magnitude was derived from this specific response.
This epitope was highly conserved: 91% conserved among M-group sequences and 78% conserved among B-subtype sequences.
Response to this epitope has been previously associated with long-term nonprogression, and escape mutations have been associated with lower CD4+ T-cell counts and higher viral loads.

References

Dinges2010 Warren L. Dinges, Julia Richardt, David Friedrich, Emilie Jalbert, Yi Liu, Claire E. Stevens, Janine Maenza, Ann C. Collier, Daniel E. Geraghty, Jeremy Smith, Zoe Moodie, James I. Mullins, M. Juliana McElrath, and Helen Horton. Virus-Specific CD8+ T-Cell Responses Better Define HIV Disease Progression than HLA Genotype. J. Virol., 84(9):4461-4468, May 2010. PubMed ID: 20147397. Show all entries for this paper.

Displaying record number 57911

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B*08)
Immunogen	peptide-HLA interaction
Experimental methods	Tetramer binding
Keywords

Notes

The study investigated whether when compound genotype HLA-Bw4 presented peptides, it could affect the interaction between the HLA and natural killer cell receptor KIR3DL1. Various HIV-1 epitopes differentially modulated the binding of KIR3DL1 to HLA-Bw4.
Bw6(B*08)-restricted epitope FLKEKGGL did not bind to KIR3DL1.

References

Fadda2011 Lena Fadda, Geraldine M. O'Connor, Swati Kumar, Alicja Piechocka-Trocha, Clair M. Gardiner, Mary Carrington, Daniel W. McVicar, and Marcus Altfeld. Common HIV-1 Peptide Variants Mediate Differential Binding of KIR3DL1 to HLA-Bw4 Molecules. J Virol, 85(12):5970-5974, Jun 2011. PubMed ID: 21471246. Show all entries for this paper.

Displaying record number 58007

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	in vitro stimulation or selection
Experimental methods	Chromium-release assay, Cytotoxicity assay, Other
Keywords	epitope processing, escape

Notes

The cytosolic stability of 166 HIV-1 epitopes was found to be highly variable. Stability was correlated with antigenicity. Stability could be modulated through mutations, and some naturally-occurring mutations affect cytosolic stability and CTL recognition; reduced stability may be associated with escape.
B*08-FL8 was selected for analysis based on having known early mutants (K5N and K5M) that were predicted to have reduced intracellular stability. Mutant 5N slightly reduced peptide half life, while 5M severely reduced half life.

References

Lazaro2011 Estibaliz Lazaro, Carl Kadie, Pamela Stamegna, Shao Chong Zhang, Pauline Gourdain, Nicole Y. Lai, Mei Zhang, Sergio A. Martinez, David Heckerman, and Sylvie Le Gall. Variable HIV Peptide Stability in Human Cytosol Is Critical to Epitope Presentation and Immune Escape. J. Clin. Invest., 121(6):2480-2492, Jun 2011. PubMed ID: 21555856. Show all entries for this paper.

Displaying record number 58277

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay, Intracellular cytokine staining, Tetramer binding
Keywords	variant cross-reactivity, characterizing CD8+ T cells

Notes

To discover a correlation between HIV-1-specific CTL repertoires and CTL clone phenotype and function, CTL specific for HIV epitopes from chronic HIV-1 ART-free subjects were evaluated for expression of markers PD-1 (programmed death-1) and IL-7Ralpha (CD127), MHC I tetramer binding, cytokine production, and proliferation profiles of the dominant and subdominant clones. Dominant clonotypes had a stably higher PD-1 and lower CD127 expression, a stronger TCR avidity, failed to survive in culture at low stimulating peptide concentrations and had a lower capacity for cross-recognition. Subdominant clonotypes, however, produced higher cytokine levels in presence of variant epitope peptides, displayed greater cross-recognition and may therefore have a greater capacity to suppress viral replication of variants.
Epitope FL8 was recognized by TRBV clonotypes of patients 10022, 10027, 10071 and 10105. Patients 10022, 10027 and 10094 had FL8 as a circulating HIV epitope sequence. Patient 10094 harbored a circulating sequence variant. In longitudinal studies, the FL8-specific dominant TRBV2 population of cells maintained high PD-1 expression whereas the subdominant clonotypes had increasing CD127 levels.

References

Conrad2011 Joseph A. Conrad, Ramesh K. Ramalingam, Rita M. Smith, Louise Barnett, Shelly L. Lorey, Jie Wei, Brenna C. Simons, Shanmugalakshmi Sadagopal, Dirk Meyer-Olson, and Spyros A. Kalams. Dominant Clonotypes within HIV-Specific T Cell Responses Are Programmed Death-1 High and CD127 Low and Display Reduced Variant Cross-Reactivity. J. Immunol., 186(12):6871-6885, 15 Jun 2011. PubMed ID: 21562156. Show all entries for this paper.

Displaying record number 58538

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	Canada
Experimental methods	Other
Keywords	characterizing CD8+ T cells, elite controllers

Notes

Dual color EliSpot testing for IL-2 and IFN-γ was used to determine whether CTL restricted by MHC Class I alleles associated with slow progression to disease, viz. B*57 and B*27, had a more poly-functional profile than other CD8+ cells in a treatment-naive cohort from Montreal. B*57/B*27-restricted CTL producing IL-2 or IFN-γ or IL-2/IFN-γ, were similar in both slow progressors (SP) and progressors. Other non-protective MHC-I-restricted CTL producing both IL-2/IFN-γ, were greater in number in SP than progressors.
Within SP, peptides restricted by both protective and non-protective MHC-I alleles elicited CTL with the same functional profile. For progressors, peptides and epitopes restricted by protective B*57/B*27 alleles stimulated a higher proportion of dual-(IL-2/IFN-γ)secreting CTL.
HLA-B*08-restricted Nef optimal epitope FLKEKGGL was tested in a dual color EliSpot and was found to elicit CTL that could produce IL-2 and/or IFN-γ.

References

Peretz2011 Yoav Peretz, Olivia Marra, Réjean Thomas, Danielle Legault, Pierre Côté, Mohamed-Rachid Boulassel, Danielle Rouleau, Jean-Pierre Routy, Rafick-Pierre Sékaly, Christos M Tsoukas, Cécile Tremblay, and Nicole F. Bernard. Relative Contribution of HIV-Specific Functional Lymphocyte Subsets Restricted by Protective and Non-Protective HLA Alleles. Viral Immunol, 24(3):189-198, Jun 2011. PubMed ID: 21668360. Show all entries for this paper.

Displaying record number 58544

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	B8-FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	United States
Experimental methods
Keywords	review, rate of progression, acute/early infection

Notes

Acute infection with HIV-1 is accompanied by high viral load (VL) and loss of CD4 helper T cells. Early inhibition of VL by CTL results in a 'set point' that is correlated with disease progression. The early CTL response during acute infection if successful is to a known immunodominant epitope. Following, chronic infection sets in with a greater breadth and magnitude of CTL response, but no change in VL or HIV-1 replication. Immunodominant epitopes from several studies that help set a lower VL during acute phase are listed in this review.
FLKEKGGL, B8-FL8, when restricted by HLA-B*08 is recognized by 74% acutely-infected and 75% chronically-infected North American subjects expressing the same HLA allele. HLA-B*08 is present at a frequency of 22.5% in North American white populations.

References

Streeck2010 Hendrik Streeck and Douglas F. Nixon. T Cell Immunity in Acute HIV-1 Infection. J. Infect. Dis., 202(Suppl 2):S302-8, 15 Oct 2010. PubMed ID: 20846037. Show all entries for this paper.

Displaying record number 58782

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	A, B, C, CRF01_AE, D, F, G, H
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	United Kingdom
Experimental methods	CD8 T-cell Elispot - IFNγ, Degranulation, CD107a and b cell surface mobilization
Keywords	subtype comparisons, epitope processing

Notes

2 Nef epitopes, FL8, FLKEKGGL and KL9, KEKGGLEGL, that overlap by 6 residues but are restricted by different HLAs (B*08 and B*40, respectively), were studied to follow the impact of extremely small shifts in position on epitope processing. Epitope-specific CTLs were tested for recognition of HLA-B*40- or B*08-restricted Nef epitopes (KL9 or FL8) from different HIV isolates. The different subtypes all carried the same epitope sequences but had minor differences in flanking sequences. Each epitope was recognized to a different extent depending on what its subtype was, and this was dependent on flanking sequences.
The same FL8 sequence from different subtypes (clades B, C, D, F, H), was recognized to different extents; and FL8 from clades A, AE and G was not recognized at all.

References

Culshaw2012 Abigail Culshaw, Tao Dong, and Sarah Louise Rowland-Jones. A 2 Amino Acid Shift in Position Leads to a Substantial Difference in the Pattern of Processing of 2 HIV-1 Epitopes. J. Acquir. Immune Defic. Syndr., 59(4):335-339, 1 Apr 2012. PubMed ID: 22217677. Show all entries for this paper.

Displaying record number 58800

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	B*08-FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	Other, Tetramer binding
Keywords

Notes

This study of post-ART TCR repertoire and clonal diversity was undertaken in 8 HIV-1 infected subjects using 14 HIV-specific CTL responses. It was noted that while circulating and memory CTL decreased along with a reduction in diversity of CTL responses, the overall hierarchy of TCR clonotypes was unchanged. A redistribution in memory phenotype did occur as well as decrease PD-1, CD38 expression, however PD-1 continued to be expressed more highly on dominant clonotypes. Therefore dominant clonotypes maintain their ability to recognize antigen post-ART, and TCR diversity also persists.
Both different clonotypes of epitope FL8 studied showed decreased numbers post-ART. Dominant clonotypes also remained remarkably constant pre- and post-ART. Small decreases in diversity of epitope-specificity of TCR were also seen pre- and post-ART in 1/2 clonotypes.

References

Conrad2012 Joseph A. Conrad, Ramesh K. Ramalingam, Coley B. Duncan, Rita M. Smith, Jie Wei, Louise Barnett, Brenna C. Simons, Shelly L. Lorey, and Spyros A. Kalams. Antiretroviral Therapy Reduces the Magnitude and T Cell Receptor Repertoire Diversity of HIV-Specific T Cell Responses without Changing T Cell Clonotype Dominance. J. Virol., 86(8):4213-4221, Apr 2012. PubMed ID: 22258246. Show all entries for this paper.

Displaying record number 59665

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	rate of progression, optimal epitope

Notes

Correlation between HLA class I and spontaneous control of HIV-1 was significant for 7-8 epitopes when 341 chronic, HIV-infected subjects, divided into controllers and non-controllers, were tested for EliSpot responses to 257 optimally defined epitopes. 21 epitopes were associated with viral progression. Protective epitopes tend to cluster in regions of critical stability for the protein, therefore constraining escape.
FLKEKGGL had a significantly positive association with HLA B*08; it was recognized by 12/20 B*08-positive subjects and 21/217 B*08-negative subjects.

References

Displaying record number 61239

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Experimental methods	Other
Keywords	review, TCR usage

Notes

Recent findings of the HIV-specific TCR repertoire are reviewed here. FLKEKGGL (FL8)-TCR repertoire are diverse and flexible and TCR gene usage is biased.

References

Lissina2016 Anna Lissina, Lisa A. Chakrabarti, Masafumi Takiguchi, and Victor Appay. TCR Clonotypes: Molecular Determinants of T-Cell Efficacy against HIV. Curr. Opin. Virol., 16:77-85, Feb 2016. PubMed ID: 26874617. Show all entries for this paper.

Displaying record number 61634

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	B08-FL8
Subtype	B
Species (MHC/HLA)	human(B*08)
Immunogen	HIV-1 infection
Country	Canada
Experimental methods	Chromium-release assay, Other
Keywords	epitope processing, escape

Notes

HIV-1 escape by an antigen processing mutation was identified and found to show increased epitope presentation and thus recognition. This HLA-B*08-restricted mutation, iSH-FLKEKGGL, at position -3, in flanking sequences of epitope LSH-FLKEKGGL, was identified by mass spectrometry, in vitro. The findings were confirmed in vivo in 1,134 ART-naive subjects.

References

Zhang2012 Shao Chong Zhang, Eric Martin, Mariko Shimada, Sasha Blue Godfrey, Jennifer Fricke, Shirley Locastro, Nicole Y. Lai, Paul Liebesny, Jonathan M. Carlson, Chanson J. Brumme, Oluwatobi Awele Ogbechie, Huabiao Chen, Bruce D. Walker, Zabrina L. Brumme, Daniel G. Kavanagh, and Sylvie Le Gall. Aminopeptidase Substrate Preference Affects HIV Epitope Presentation and Predicts Immune Escape Patterns in HIV-Infected Individuals. J. Immunol., 188(12):5924-5934, 15 Jun 2012. PubMed ID: 22586036. Show all entries for this paper.

Displaying record number 55006

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	FLK
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	rate of progression, TCR usage, variant cross-reactivity, characterizing CD8+ T cells

Notes

Functional cross-reactivity of CD8 responses to HIV-1 epitopes restricted by different HLA-alleles was analyzed. It was shown that epitope-specific responses with the most efficient cross-recognition were strongly associated with delayed disease progression. Variant-cross recognition efficiency was linked to the dominant TCRs used for epitope recognition. Epitopes restricted by the same HLA-allele did not show similar variant cross-recognition efficiency, suggesting that the rate of disease progression might be associated with the quality of responses to certain critical epitopes.
This epitope, B8-FLK that is associated with more rapid progression to AIDS and its natural as well as alanine-substituted variants were quite weakly cross-recognized. CTLs responding to this epitope expressed the same predominant TCR Vbeta family.

References

Turnbull2006 Emma L. Turnbull, A. Ross Lopes, Nicola A. Jones, David Cornforth, Phillipa Newton, Diana Aldam, Pierre Pellegrino, Jo Turner, Ian Williams, Craig M. Wilson, Paul A. Goepfert, Mala K. Maini, and Persephone Borrow. HIV-1 Epitope-Specific CD8+ T Cell Responses Strongly Associated with Delayed Disease Progression Cross-Recognize Epitope Variants Efficiently. J. Immunol., 176(10):6130-6146, 15 May 2006. PubMed ID: 16670322. Show all entries for this paper.

Displaying record number 53825

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Subtype	B
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Patient MHC/HLA	A0101, B0801
Country	United Kingdom
Experimental methods	CD8 T-cell Elispot - IFNγ, HLA binding
Keywords	escape, acute/early infection

Notes

CTL responses and escape were analyzed in 4 homosexual couples where blood samples were available within weeks of estimated transmission. When the recipient had the same HLA type as the donor, CTL escape variants prevented a CTL response to those epitopes in the recipient. Even when the HLA alleles were different in the transmitting couple, a single escape mutation in one epitope can abolish CTL recognition of an overlapping epitope of distinct restriction in the recipient. In an early acute infection of the donor, the precise timing of transmission determines the viral variants transmitted.
The recipient mounted an acute CTL response to this epitope, and the escape variant flkeQggl emerged soon after.

References

Milicic2005 Anita Milicic, Charles T. T. Edwards, Stéphane Hué, Julie Fox, Helen Brown, Tilly Pillay, Jan W. Drijfhout, Jonathan N. Weber, Edward C. Holmes, Sarah J. Fidler, Hua-Tang Zhang, and Rodney E. Phillips. Sexual Transmission of Single Human Immunodeficiency Virus Type 1 Virions Encoding Highly Polymorphic Multisite Cytotoxic T-Lymphocyte Escape Variants. J. Virol., 79(22):13953-13962, Nov 2005. PubMed ID: 16254331. Show all entries for this paper.

Displaying record number 60941

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Patient MHC/HLA	71101: A0101, A0301, B0801, B3503, Cw0401, Cw0701; 44149: A0101, A2401, B0701, B0801, Cw0701, Cw0702; 67200: A0101, A2401, B0801, B5701, Cw0602, Cw0701; 32645: A0101, A0201, B0801, B3503, Cw0401, Cw0701
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	acute/early infection

Notes

The extent to which set-point viremia is affected by early HIV-infection T cell responses to either conserved or variable epitopes was studied. 23 ART-naive subjects were characterized for CTL responses for 6 months, postinfection. While most CTL responses (73/123) were targeted against variable HIV-1 epitopes, recognition of conserved epitopes (16/123) was associated with lower set point viremia. This was independent of HLA type and also functional avidity of the CTL response. Most of the conserved responses were targeted to Gag and Pol epitopes.
FLKEKGGL, restricted by B*0801, was recognized by 4 patients with the restricting allele.

References

Kunwar2013 Pratima Kunwar, Natalie Hawkins, Warren L. Dinges, Yi Liu, Erin E. Gabriel, David A. Swan, Claire E. Stevens, Janine Maenza, Ann C. Collier, James I. Mullins, Tomer Hertz, Xuesong Yu, and Helen Horton. Superior Control of HIV-1 Replication by CD8+ T Cells Targeting Conserved Epitopes: Implications for HIV Vaccine Design. PLoS One, 8(5):e64405, 2013. PubMed ID: 23741326. Show all entries for this paper.

Displaying record number 61628

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	B*08-FL8
Subtype	C
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	South Africa
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	elite controllers

Notes

70 HIV-C-infected ART-naive South African viremic controllers (VC) of whom 50% carried protective HLA-I alleles were studied longitudinally for 5 years to show that mechanism of viral load (VL) control is different between protective-HLA I-carrying and nonprotective-HLA I-carrying VCs. While control by protective HLA-I carrying VCs is driven primarily by broad, anti-Gag CTL responses with potent ex vivo viral inhibition, control in subjects without protective HLA I may be durable but CTL-independent.
Progression in VCs is generally precipitated by CTL escape and lowered antivrial efficacy seen as loss of CTL polyfunctionality, proliferation and ex vivo suppression of HIV-1 replication around virologic failure. Epitopes targeted before and after virologic failure are listed in Tables 2, 3 and 4 on pages 6824, 6825, 6826.
Optimal Nef epitope, B*08-FLKEKGGL (FL8) was targeted by subject SK-187, a failing VC, before and after loss of viremic control (EliSpots = 640/763 sfu/10⁶); and by subject SK-275 only before loss of control (120 sfu/10⁶).

References

Koofhethile2016 Catherine K. Koofhethile, Zaza M. Ndhlovu, Christina Thobakgale-Tshabalala, Julia G. Prado, Nasreen Ismail, Zenele Mncube, Lungile Mkhize, Mary van der Stok, Nonhlanhla Yende, Bruce D. Walker, Philip J. R. Goulder, and Thumbi Ndung'u. CD8+ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles. J. Virol., 90(15):6818-6831, 1 Aug 2016. PubMed ID: 27194762. Show all entries for this paper.

Displaying record number 55171

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	South Africa
Experimental methods	Intracellular cytokine staining, Proliferation, Tetramer binding
Keywords

Notes

PD-1 (inhibitory receptor programmed death) expression on CD8 and CD4 cells was studied. There was a positive correlation with viral load and inverse correlation with CD4 T cell count, and blockage of PD-1 pathway augmented CD4 and CD8 T cell function.

References

Day2006 Cheryl L. Day, Daniel E. Kaufmann, Photini Kiepiela, Julia A. Brown, Eshia S. Moodley, Sharon Reddy, Elizabeth W. Mackey, Joseph D. Miller, Alasdair J. Leslie, Chantal DePierres, Zenele Mncube, Jaikumar Duraiswamy, Baogong Zhu, Quentin Eichbaum, Marcus Altfeld, E. John Wherry, Hoosen M. Coovadia, Philip J. R. Goulder, Paul Klenerman, Rafi Ahmed, Gordon J. Freeman, and Bruce D. Walker. PD-1 Expression on HIV-Specific T Cells Is Associated with T-Cell Exhaustion and Disease Progression. Nature, 443(7109):350-354, 21 Sep 2006. PubMed ID: 16921384. Show all entries for this paper.

Displaying record number 58854

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	Canada
Experimental methods	Flow cytometric T-cell cytokine assay, Intracellular cytokine staining, Tetramer binding
Keywords	characterizing CD8+ T cells

Notes

Gene array studies were conducted in 35 subjects, comparing their immune expression in CTLs from acute/early infection to chronically-infected CTL. It was found that profound metabolic, proliferative and apoptotic-susceptibility differences existed. Acute/early CTL secreted less γ-IFN, but were more cytotoxic. IL-7R expression and ability to secrete IL-2 were correlated with viral set point. Stress and hyperproliferation negatively affect the transition from early/acute to chronic functional CTLs.
HLA-B*0801-QVPLRPMTYK tetramers were used to determine CTLs and their ability to secrete cytokines upon stimulation with QK10.

References

Trautmann2012 Lydie Trautmann, Florentin-Martial Mbitikon-Kobo, Jean-Philippe Goulet, Yoav Peretz, Yu Shi, Julien Van Grevenynghe, Francesco Andrea Procopio, Mohamad Rachid Boulassel, Jean-Pierre Routy, Nicolas Chomont, Elias K. Haddad, and Rafick-Pierre Sekaly. Profound Metabolic, Functional, and Cytolytic Differences Characterize HIV-Specific CD8 T Cells in Primary and Chronic HIV Infection. Blood, 120(17):3466-3477, 25 Oct 2012. PubMed ID: 22955926. Show all entries for this paper.

Displaying record number 58985

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	Australia, Canada, Spain, Switzerland
Experimental methods	Other
Keywords	mutation acquisition

Notes

Computational genome-wide scans were run to find associations between (subjects' ) host genome DNA polymorphisms, and infecting HIV-1 genome sequence variation from 1071 subjects, as well as their viral load (VL). Such genome-to-genome approaches also reveal sites of single nucleotide polymorphisms (SNPs) linked to variant HIV-1 amino acids that either limit viral efficiency or that are easily tolerated by it.
48 amino acid residues of HIV-1 were linked to human SNPs, and the variants were not antiretroviral drug resistance mutations. 50% of these viral amino acids were located within previously defined optimal epitopes, such as FLKEKGGL, whose variation at position 94 is associated with SNP rs9265972.

References

Bartha2013 István Bartha, Jonathan M. Carlson, Chanson J. Brumme, Paul J. McLaren, Zabrina L. Brumme, Mina John, David W. Haas, Javier Martinez-Picado, Judith Dalmau, Cecilio López-Galíndez, Concepción Casado, Andri Rauch, Huldrych F. Günthard, Enos Bernasconi, Pietro Vernazza, Thomas Klimkait, Sabine Yerly, Stephen J. O'Brien, Jennifer Listgarten, Nico Pfeifer, Christoph Lippert, Nicolo Fusi, Zoltán Kutalik, Todd M. Allen, Viktor Müller, P. Richard Harrigan, David Heckerman, Amalio Telenti, and Jacques Fellay. A Genome-to-Genome Analysis of Associations between Human Genetic Variation, HIV-1 Sequence Diversity, and Viral Control. eLife, 2:e01123, 2013. PubMed ID: 24171102. Show all entries for this paper.

Displaying record number 54074

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	( C consensus)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	C
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	South Africa
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	rate of progression, optimal epitope

Notes

A comprehensive analysis of 160 class I T cell responses in 578 individuals from KwaZulu-Natal, South Africa was performed. Gag-specific responses were associated with lowering viremia, while Env, accessory and regulatory protein-specific responses were associated with higher viremia.
FLKEKGGL is an optimal epitope.

References

Kiepiela2007 Photini Kiepiela, Kholiswa Ngumbela, Christina Thobakgale, Dhanwanthie Ramduth, Isobella Honeyborne, Eshia Moodley, Shabashini Reddy, Chantal de Pierres, Zenele Mncube, Nompumelelo Mkhwanazi, Karen Bishop, Mary van der Stok, Kriebashnie Nair, Nasreen Khan, Hayley Crawford, Rebecca Payne, Alasdair Leslie, Julia Prado, Andrew Prendergast, John Frater, Noel McCarthy, Christian Brander, Gerald H. Learn, David Nickle, Christine Rousseau, Hoosen Coovadia, James I. Mullins, David Heckerman, Bruce D. Walker, and Philip Goulder. CD8+ T-Cell Responses to Different HIV Proteins Have Discordant Associations with Viral Load. Nat. Med., 13(1):46-53, Jan 2007. PubMed ID: 17173051. Show all entries for this paper.

Displaying record number 53190

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	FL8
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Patient MHC/HLA	A0201, A2402, B0801, B5701, Cw0602, Cw0701; A0101, A0201, B0801, B5701, Cw0602, Cw0701; A2, A2402, B0801, B15, Cw12, Cw7; A0101, A0201, B0801, B5701, Cw0602, Cw0701
Country	United Kingdom
Experimental methods	CD8 T-cell Elispot - IFNγ, Chromium-release assay, Flow cytometric T-cell cytokine assay, Tetramer binding
Keywords	rate of progression, escape, TCR usage, characterizing CD8+ T cells

Notes

In 4 donors with delayed disease progression, the response to the FL8 Nef epitope was dominated by V-beta-13.2 TCR expressing CTLs with an unusually long CDR3 region. These CTLs were shown to be resistant to apoptosis and able to recognize escape variants of the FL8 Nef epitope. Thus, selection of these CTLs may be related to better clinical outcome.
The Q5 variant flkeQggl was rapidly selected in a donor that responded to the FLKEKGGL epitope. The FLKEKGGL peptide and the variant flkeQggl HLA-B8 complexes bound to the Vbeta13.2 FLKEKGGL TCR with equal affinity, while the Vbeta6 FLKEKGGL TCR had reduced affinity for the FLKEKGGL form and did not recognize the Q5 variant. Other variants (T5, N5, and M5 as well as Q5) were recognized by Vbeta13.2 clones from all 4 donors. One clone from donor 046 that was not Vbeta13.2 could only recognize the index variant.

References

Dong2004 Tao Dong, Guillaume Stewart-Jones, Nan Chen, Philippa Easterbrook, Xiaoning Xu, Laura Papagno, Victor Appay, Michael Weekes, Chris Conlon, Celsa Spina, Susan Little, Gavin Screaton, Anton van der Merwe, Douglas D. Richman, Andrew J. McMichael, E. Yvonne Jones, and Sarah L. Rowland-Jones. HIV-Specific Cytotoxic T Cells from Long-Term Survivors Select a Unique T Cell Receptor. J. Exp. Med., 200(12):1547-1557, 20 Dec 2004. PubMed ID: 15596521. Show all entries for this paper.

Displaying record number 59178

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	nef 90-97
Subtype	B
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	France
Experimental methods	CD8 T-cell Elispot - IFNγ, CTL suppression of replication, HLA binding, Intracellular cytokine staining, Other
Keywords	binding affinity, elite controllers

Notes

49 HLA-B*57⁺ and 52 HLA-B*57^- ART-naive HIV controllers (HIC) from the French ANRS CODEX cohort were compared to determine various impacts of B*57 and non-B*57 alleles on HIV-specific CTL responses (e.g. activation and differentiation markers, proliferation potential, cytokine production and HIV-suppression). HLA-B*57⁺ chronic progressors were the control group.
CTL response was higher in HLA-B*57⁺ than -B*57^- subjects, most of them Gag-specific. 80% of all such responses were restricted by -B*57^- Gag or Nef epitopes.
Greater frequency of as well as stronger CTL responses correlated with higher functional avidity of TCR-peptide interaction. B*57-restricted responses were 1 log more sensitive than non-B*57-restricted responses regardless of whether subjects were HLA-B*57⁺ or -B*57^-, and led to higher proliferation of CTL, higher IL-2 production, higher frequency of IFN-γ-producing cells, higher degree of differentiation with more CD127 (and as seen by higher markers for central memory cells, CCR7⁺CD45RO⁺ / effector memory cells, CCR7⁺CD27⁺CD45RO⁺ / senescent cells, CD57⁺). Activation markers CD38 and HLA-DR however, remained the same between CTL restricted by HLAs -B*57 or not.
Higher TCR-peptide avidity was correlated also to HICs as compared to progressors - with proliferation, IL-2 production and CD127 levels being affected in HLA-B*57-restricted responding CTL.
Viral replication suppression was seen in all HIC whether HLA-B*57⁺ or -B*57^-. Strong viral suppression (SVS) correlates with lower plasma viral load.
HLA-B*0801-restricted peptide nef 90-97, FLKEKGGL, was recognized by both B*57⁺ and B*57^- subjects with varying intensities.

References

Lecuroux2014 Camille Lécuroux, Asier Sáez-Cirión, Isabelle Girault, Pierre Versmisse, Faroudy Boufassa, Véronique Avettand-Fenoël, Christine Rouzioux, Laurence Meyer, Gianfranco Pancino, Olivier Lambotte, Martine Sinet, and Alain Venet. Both HLA-B*57 and Plasma HIV RNA Levels Contribute to the HIV-Specific CD8+ T Cell Response in HIV Controllers. J. Virol., 88(1):176-187, Jan 2014. PubMed ID: 24131719. Show all entries for this paper.

Displaying record number 53287

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	( C consensus)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	C
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	South Africa
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	characterizing CD8+ T cells

Notes

HLA class I restricted CD8+ T-cell responses against HIV-1 were analyzed in African patients. Significantly more responses were shown to be HLA-B restricted. Viral load, CD4 count, and thus rate of disease progression were also associated with HLA-B alleles. In addition, the selection pressure imposed on HIV-1 by HLA-B alleles was shown to be substantially greater than by other alleles.
This epitope was suggested to be the epitope within a longer reactive peptide based on correspondence with a known epitope in the HIV database. Also, a significantly higher frequency of people in the Durban cohort who reacted with the peptide had this HLA type.

References

Kiepiela2004 Photini Kiepiela, Alasdair J. Leslie, Isobella Honeyborne, Danni Ramduth, Christina Thobakgale, Senica Chetty, Prinisha Rathnavalu, Corey Moore, Katja J. Pfafferott, Louise Hilton, Peter Zimbwa, Sarah Moore, Todd Allen, Christian Brander, Marylyn M. Addo, Marcus Altfeld, Ian James, Simon Mallal, Michael Bunce, Linda D. Barber, James Szinger, Cheryl Day, Paul Klenerman, James Mullins, Bette Korber, Hoosen M. Coovadia, Bruce D. Walker, and Philip J. R. Goulder. Dominant Influence of HLA-B in Mediating the Potential Co-Evolution of HIV and HLA. Nature, 432(7018):769-775, 9 Dec 2004. LA-UR 04-5920. PubMed ID: 15592417. Show all entries for this paper.

Displaying record number 57954

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	FL8
Subtype	A, B
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	Australia
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	escape, HLA associated polymorphism

Notes

Epitopes that have undergone escape are often still immunogenic. Scanning for epitopes that encompass HLA-specific polymorphisms revealed 97 HLA-polymorphism associations in which the mutation resulted in the creation rather than abolition of an epitope, termed a "neo-epitope". This study examined 9 neo-epitopes that were well-characterized optimal epitopes that elicit T-cell responses in chronic infection. HIV-1 adaptation not only abrogates the immune recognition of early targeted epitopes, but may also increase immune recognition to other epitopes, which elicit immunodominant but non-protective T-cell responses.
FLKEKGGL underwent classical escape, with adapted forms FLKEqGGL, FLKEeGGL, and FLKEnGGL having abrogated EliSpot responses.
Longitudinal study of an acute subtype A infection in a B*08-positive patient revealed early responses to FLKEKGGL and its variant, FLKEnGGL. The patient's sequences were the non-adapted form and remained invariant despite high-magnitude responses.

References

Keane2012 Niamh M. Keane, Steven G. Roberts, Coral-Ann M. Almeida, Tanya Krishnan, Abha Chopra, Emma Demaine, Rebecca Laird, Monika Tschochner, Jonathan M. Carlson, Simon Mallal, David Heckerman, Ian James, and Mina John. High-Avidity, High-IFN-gamma-Producing CD8 T-Cell Responses following Immune Selection during HIV-1 Infection. Immunol. Cell Biol., 90(2):224-234, Feb 2012. PubMed ID: 21577229. Show all entries for this paper.

Displaying record number 1016

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(89-97 LAI)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Experimental methods
Keywords	optimal epitope

Notes

C. Brander notes this is a B*0801 epitope.

References

Llano2019 Anuska Llano, Samandhy Cedeño, Sandra Silva Arrieta, and Christian Brander. The 2019 Optimal HIV CTL Epitopes Update: Growing Diversity in Epitope Length and HLA restriction. 2019. Show all entries for this paper.

Displaying record number 57100

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97 DU422)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B*0801)
Immunogen	in vitro stimulation or selection
Experimental methods	CD8 T-cell Elispot - IFNγ, Chromium-release assay, Tetramer binding
Keywords	dendritic cells

Notes

Three types of myeloid dendritic cells - monocytic dendritic cells, Langerhans cells, and interstitial dermal-intestinal dendritic cells - were shown to be able to prime CD8+ T-cell responses to HIV-1. Primed monocytic dendritic cells from 2 uninfected adult donors had broad primary T-cell reactivity, reacting with 15mers containing 42 known epitopes in Gag, Env, and Nef.
One of the reactive 15mers contained optimal epitope FLKEKGGL, which was restricted by HLA B*0801.

References

Colleton2009 Bonnie A. Colleton, Xiao-Li Huang, Nada M. Melhem, Zheng Fan, Luann Borowski, Giovanna Rappocciolo, and Charles R. Rinaldo. Primary Human Immunodeficiency Virus Type 1-Specific CD8+ T-Cell Responses Induced by Myeloid Dendritic Cells. J. Virol., 83(12):6288-6299, Jun 2009. PubMed ID: 19357176. Show all entries for this paper.

Displaying record number 57376

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	B8-FL8 wt
Species (MHC/HLA)	human(B*0801)
Immunogen	in vitro stimulation or selection, peptide-HLA interaction
Country	United States
Experimental methods	Other
Keywords	binding affinity, escape

Notes

Change of interactions between peptide/MHC Class I complexes and the inhibitory myelomonocytic MHC I receptor ILT4 were analyzed in 4 immunodominant HIV-1 CTL complexes. Escape due to CTL-mediated immune pressure in 3 of the epitopes consistently enhanced binding to alternative MHC Class I receptor ILT4 which caused defects in the antigen presenting properties of monocytes and dendritic cells (DC). CTL escape mutations therefore have regulatory effects on the function of monocytes and DC.
Both B8-FL8 epitope (FLKEKGGL) escapes (FLKEeGGL and FLrEKGGL) increased binding to ILT4 on CD14+ monocytes as determined by fluorophore labeling.
This study suggests that such immunoregulatory effects of CTL escape should be considered before selecting variants for HIV-1 vaccines.

References

Yang2010 Yue Yang, Jinghe Huang, Ildiko Toth, Mathias Lichterfeld, and Xu G. Yu. Mutational Escape in HIV-1 CTL Epitopes Leads to Increased Binding to Inhibitory Myelomonocytic MHC Class I Receptors. PLoS One, 5(12):e15084, 2010. PubMed ID: 21170342. Show all entries for this paper.

Displaying record number 54607

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	C
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	South Africa
Experimental methods	CD8 T-cell Elispot - IFNγ, Degranulation, CD107a and b cell surface mobilization, Intracellular cytokine staining, Proliferation, Tetramer binding
Keywords	rate of progression

Notes

Eight epitopes and 113 subjects were used to test whether correlations existed between HIV-1 Clade C viral load and CTL proliferation, cytokine production or degranulation in therapy-naive patients. Only CTL proliferation showed a strong inverse correlation with viral load.
The tetramer B*0801 FL8 was used to test 26 patients and gave a median ex vivo tetramer frequency of 0.40.

References

Day2007 Cheryl L. Day, Photini Kiepiela, Alasdair J. Leslie, Mary van der Stok, Kriebashne Nair, Nasreen Ismail, Isobella Honeyborne, Hayley Crawford, Hoosen M. Coovadia, Philip J. R. Goulder, Bruce D. Walker, and Paul Klenerman. Proliferative Capacity of Epitope-Specific CD8 T-cell Responses Is Inversely Related to Viral Load in Chronic Human Immunodeficiency Virus Type 1 Infection. J. Virol., 81(1):434-438, Jan 2007. PubMed ID: 17050606. Show all entries for this paper.

Displaying record number 61994

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B*0801)
Immunogen	peptide-HLA interaction
Experimental methods	Intracellular cytokine staining, Other
Keywords	assay or method development, NK cells

Notes

Contamination of what were previously thought to be highly specific epitopes identified through HLA IP-based immunopeptidomics is exposed. A low-level of co-isolation of erroneously assigned Class I-restricted peptides is found viz. HLA class II peptides, extended peptides from HIV Gag, and peptides from the B lymphoblastoid cell line 721.221 previously thought to be Class I deficient but which actually does present HLA-Cw*0102.
9/64 C8166 cell lysate identified epitopes are actually known epitopes. FLKEKGGL is one of them, restricted by B*0801.

References

Partridge2018 Thomas Partridge, Annalisa Nicastri, Anna E. Kliszczak, Louis-Marie Yindom, Benedikt M. Kessler, Nicola Ternette, and Persephone Borrow. Discrimination Between Human Leukocyte Antigen Class I-Bound and Co-Purified HIV-Derived Peptides in Immunopeptidomics Workflows. Front. Immunol., 9:912, 2018. PubMed ID: 29780384. Show all entries for this paper.

Displaying record number 57807

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B*0801)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	computational epitope prediction, HLA associated polymorphism

Notes

From a large study of HLA-associated polymorphisms, 431 putative epitopes with good EpiPred scores were selected; 320 of these were tested for IFNgamma EliSpot responses in subjects carrying the predicted HLA.
Peptides with response rate >40% (comparable with mean response rate of 33% for known epitopes) and tested in 5 or more individuals with respective HLA were considered in this study as probable novel epitopes and entered in the database. 41 additional "possible" novel epitopes for which either <5 individuals were tested or response rate was below 40%, are not entered in the database.
There was a markedly higher proportion of putative epitopes in Nef, and the Nef epitopes tended to have the most high-magnitude EliSpot responses. Among 33 epitopes that elicited a response in over 40% out of 5 or more individuals tested, over 61% clustered in Nef.
Epitope FLKEKGGL was recognized by 8/11 B*0801-positive HIV-1-infected patients.

References

Almeida2011 Coral-Ann M. Almeida, Corine Bronke, Steven G. Roberts, Elizabeth McKinnon, Niamh M. Keane, Abha Chopra, Carl Kadie, Jonathan Carlson, David W. Haas, Sharon A. Riddler, Richard Haubrich, David Heckerman, Simon Mallal, and Mina John. Translation of HLA-HIV Associations to the Cellular Level: HIV Adapts to Inflate CD8 T Cell Responses against Nef and HLA-Adapted Variant Epitopes. J. Immunol., 187(5):2502-2513, 1 Sep 2011. PubMed ID: 21821798. Show all entries for this paper.

Displaying record number 54751

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B*0801)
Immunogen	peptide-HLA interaction
Experimental methods	Tetramer binding
Keywords	binding affinity

Notes

MHC can exert a protective effect on HIV-1 disease progression by the interaction of MHC Class I molecules with Killer Inhibitory Receptors (KIR) of the innate immune system. Here, KIR3DS1, a putative stimulatory receptor and allele of the inhibitory KIR3DL1, is studied. Bw4 MHC Class I proteins were implicated in this KIR's ligand specificity, but the authors were unable to generate binding of Bw4Ile80 tetramers in complex with epitopes to KIR3DS1 transiently expressed on 293-T cells, using a panel of HIV-epitopes differing at p7 and p8.
This epitope, FLKEKGGL (MHC Class I restriction, serotype Bw6) complexed with MHC B*0801 as a tetramer was unable to bind KIR3DS1 at 4, 20 and 37C.

References

Gillespie2007 Geraldine M. A. Gillespie, Arman Bashirova, Tao Dong, Daniel W. McVicar, Sarah L. Rowland-Jones, and Mary Carrington. Lack of KIR3DS1 Binding to MHC Class I Bw4 Tetramers in Complex with CD8+ T Cell Epitopes. AIDS Res. Hum. Retroviruses, 23(3):451-455, Mar 2007. PubMed ID: 17411378. Show all entries for this paper.

Displaying record number 59669

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B3501, B3508)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	rate of progression, optimal epitope

Notes

Correlation between HLA class I and spontaneous control of HIV-1 was significant for 7-8 epitopes when 341 chronic, HIV-infected subjects, divided into controllers and non-controllers, were tested for EliSpot responses to 257 optimally defined epitopes. 21 epitopes were associated with viral progression. Protective epitopes tend to cluster in regions of critical stability for the protein, therefore constraining escape.
FLKEKGGL had a significantly positive association with HLA B*3501,B*3508; it was recognized by 4/31 B*3501,B*3508-positive subjects and 4/137 B*3501,B*3508-negative subjects.

References

Displaying record number 59668

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B*40)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	rate of progression, optimal epitope

Notes

Correlation between HLA class I and spontaneous control of HIV-1 was significant for 7-8 epitopes when 341 chronic, HIV-infected subjects, divided into controllers and non-controllers, were tested for EliSpot responses to 257 optimally defined epitopes. 21 epitopes were associated with viral progression. Protective epitopes tend to cluster in regions of critical stability for the protein, therefore constraining escape.
FLKEKGGL had a significantly positive association with HLA B*40; it was recognized by 4/22 B*40-positive subjects and 8/168 B*40-negative subjects.

References

Displaying record number 59666

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B*57)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	rate of progression, optimal epitope

Notes

Correlation between HLA class I and spontaneous control of HIV-1 was significant for 7-8 epitopes when 341 chronic, HIV-infected subjects, divided into controllers and non-controllers, were tested for EliSpot responses to 257 optimally defined epitopes. 21 epitopes were associated with viral progression. Protective epitopes tend to cluster in regions of critical stability for the protein, therefore constraining escape.
FLKEKGGL had a significantly positive association with HLA B*57; it was recognized by 40/104 B*57-positive subjects and 33/237 B*57-negative subjects.

References

Displaying record number 52853

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97 B consensus)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	vaccine
Experimental methods	Chromium-release assay, Flow cytometric T-cell cytokine assay
Keywords	dynamics, escape, mutation acquisition

Vaccine Details

Vaccine type	adeno-associated virus (AAV)
Vaccine component	gp120

Notes

HIV-1 gp120 is shown to suppress the ability of antigen-specific CTLs to migrate or remain at sites of high viral replication by concentration-dependent chemotaxis and fugetaxis. Directional T-cell movement is shown to depend on the interaction of the V2 and V3 loops with the CXCR4 receptor. X4 HIV-1 gp120 causes the migration of T-cells, including HIV-1 specific CTL, away from infected target cells, another potential mechanism for immune evasion.

References

Brainard2004 Diana M. Brainard, William G. Tharp, Elva Granado, Nicholas Miller, Alicja K. Trocha, Xiang-Hui Ren, Brian Conrad, Ernest F. Terwilliger, Richard Wyatt, Bruce D. Walker, and Mark C. Poznansky. Migration of Antigen-Specific T Cells away from CXCR4-Binding Human Immunodeficiency Virus Type 1 gp120. J. Virol., 78(10):5184-5193, May 2004. PubMed ID: 15113900. Show all entries for this paper.

Displaying record number 53156

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Subtype	B
Species (MHC/HLA)	(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords	binding affinity, review, escape, characterizing CD8+ T cells

Notes

Evidence of the evolutionary adaptation of HIV-1 to the specific neutralizing antibody response and CTL detection is reviewed. Both SIV and HIV epitopes are discussed, with a detailed summary of one patient's response and CTL escape in the FLKEKGGL epitope. The three C-terminal amino acids were left unchanged, and it may be due to high fitness costs as these are putatively involved in CD4 down-regulation and formation of a hydrophobic pocket in Nef. The N terminal residue is involved in binding to protein tyrosine kinases.
Immediately after infection the susceptible epitope FLKEKGGL was found in 20/20 viral sequences. Six months later, it was only found in 4/44 sequences. The flkeNggL form was most common, 24/44 cases; it bound poorly to HLA B08 and was poorly recognized by CTL. Two minor variants were found 3/44 times, flkeEggl and flkeQggl; both bound poorly to B08, but the K->Q substitution was still well recognized. A variant flkDkggl was found in 4/44 sequences; it bound B08 moderately well, but was poorly recognized. 3 double mutants were found once each, and were not recognized by CTL: fIkeNggL, flEeNggL, and flkGNggL.

References

daSilva2003 Jack da Silva. The Evolutionary Adaptation of HIV-1 to Specific Immunity. Curr. HIV Res., 1(3):363-371, Jul 2003. PubMed ID: 15046259. Show all entries for this paper.

Displaying record number 53187

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(89-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ, Cytokine production, Flow cytometric T-cell cytokine assay, Intracellular cytokine staining, Proliferation, Tetramer binding
Keywords	HAART, ART, memory cells, characterizing CD8+ T cells

Notes

CD4+ and CD8+ responses in chronically HIV-1 infected patients on HAART were weak with decreased polyclonality. Only 33% of patients had CD4+ T-cells that could proliferate, and only 22% had HIV-specific CD8+ T-cells T-cell responses, and those rare responses showed low perforin levels and persistent expression of CD27, indicating incomplete differentiation and loss of lytic function.

References

Daniel2004 Nathalie Daniel, Bénédicte Charmeteau, Sophie Grabar, Gilles Pialoux, Dominique Salmon, Nelly Bonilla, Marion Dupuis, Christelle Troadec, Willy Rozenbaum, Hanne Gahéry-Ségard, Jean-Gérard Guillet, and Muriel Andrieu. Use of Well-Defined HIV-Derived Epitopes to Evaluate CD4+ and CD8+ T Cell Responses in Patients with Chronic HIV-1 Infection Treated with HAART. AIDS Res. Hum. Retroviruses, 20(8):827-835, Aug 2004. PubMed ID: 15320987. Show all entries for this paper.

Displaying record number 53338

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ, Proliferation, Tetramer binding
Keywords	immunodominance, acute/early infection, characterizing CD8+ T cells

Notes

HIV-1 specific CD8+ T-cells in acute and long-term nonprogressive HIV-1 infection show strong ex-vivo proliferative capacities which are rapidly lost in chronic HIV-1 infection. The loss of CD8+ T-cell function is closely linked with the loss of HIV-1 specific, IL2 secreting CD4+ T-cells. The function can be rescued in vitro and in vivo by restoring the specific CD4+ T-cell help.
Full CD8+ T-cell responses to this epitope were dependent on co-stimulation with a CD4+ T cell dependent epitope from T-cells harvested during acute infection. The CD8+ T-cell response to this epitope was immunodominant in one study individual.

References

Lichterfeld2004 Mathias Lichterfeld, Daniel E. Kaufmann, Xu G. Yu, Stanley K. Mui, Marylyn M. Addo, Mary N. Johnston, Daniel Cohen, Gregory K. Robbins, Eunice Pae, Galit Alter, Alysse Wurcel, David Stone, Eric S. Rosenberg, Bruce D. Walker, and Marcus Altfeld. Loss of HIV-1-Specific CD8+ T Cell Proliferation after Acute HIV-1 Infection and Restoration by Vaccine-Induced HIV-1-Specific CD4+ T Cells. J. Exp. Med., 200(6):701-12, Sep 20 2004. PubMed ID: 15381726. Show all entries for this paper.

Displaying record number 53359

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	( B consensus)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Patient MHC/HLA	A2, A3, B62, B8, Cw10, Cw7; A11, A29, B44, B8, Cw4, Cw7; A25, A32, B14, B8, Cw7, Cw8; A1, A3, B14, B8, Cw7, Cw8
Experimental methods	Chromium-release assay, Cytokine production, Flow cytometric T-cell cytokine assay, Intracellular cytokine staining
Keywords	assay or method development, memory cells, characterizing CD8+ T cells

Notes

Using a flow-cytometric cytotoxicity assay based on caspase-3 activation in dying target cells, it was shown that the subset of HIV-1-specific CD8+ T cells secreting both IFN-gamma and TNF-alpha exhibit stronger cytotoxic activity than those secreting only IFN-gamma. These cells also exhibited stronger intracellular perforin expression. No association between HIV-1-specific CD8+ T-cell maturation phenotypes and intracellular perforin expression was found.
4/9 individuals recognized this epitope, presented by HLA-B8.

References

Lichterfeld2004b Mathias Lichterfeld, Xu G. Yu, Michael T. Waring, Stanley K. Mui, Mary N. Johnston, Daniel Cohen, Marylyn M. Addo, John Zaunders, Galit Alter, Eunice Pae, Daryld Strick, Todd M. Allen, Eric S. Rosenberg, Bruce D. Walker, and Marcus Altfeld. HIV-1-Specific Cytotoxicity Is Preferentially Mediated by a Subset of CD8+ T Cells Producing both Interferon-gamma and Tumor Necrosis Factor-alpha. Blood, 104(2):487-394, 15 Jul 2004. PubMed ID: 15059848. Show all entries for this paper.

Displaying record number 53405

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Country	United Kingdom
Experimental methods	Intracellular cytokine staining, T-cell Elispot, Tetramer binding
Keywords	rate of progression, acute/early infection, characterizing CD8+ T cells

Notes

Acute HIV-1 infection induces massive activation of HIV-specific and non-HIV-specific CD8+ T-cells resulting in differentiation of these cells. High differentiation of CD8+ T-cells is correlated with disease progression. Differentiation is a natural process but it can be driven by elevated immune activation, such as in HIV infection.

References

Papagno2004 Laura Papagno, Celsa A. Spina, Arnaud Marchant, Mariolina Salio, Nathalie Rufer, Susan Little, Tao Dong, Gillian Chesney, Anele Waters, Philippa Easterbrook, P. Rod Dunbar, Dawn Shepherd, Vincenzo Cerundolo, Vincent Emery, Paul Griffiths, Christopher Conlon, Andrew J. McMichael, Douglas D. Richman, Sarah L. Rowland-Jones, and Victor Appay. Immune Activation and CD8+ T-Cell Differentiation towards Senescence in HIV-1 Infection. PLoS Biol., 2(2):E20, Feb 2004. PubMed ID: 14966528. Show all entries for this paper.

Displaying record number 53542

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	subtype comparisons, escape, characterizing CD8+ T cells, viral fitness and reversion

Notes

Two-thirds of all mutations arising in non-envelope proteins during the transition from acute to chronic infection were found to be due to either CD8 T-cell-associated selective pressures or reversion of HLA-I-associated mutations selected in a previous host.The predominance of escape mutations at highly polymorphic sites was observed across different HIV-1 clades.
One escape mutation, at position 5, FLKEnGGL, was found not to correspond to the most polymorphic residue in the epitope.

References

Allen2005a Todd M. Allen, Marcus Altfeld, Shaun C. Geer, Elizabeth T. Kalife, Corey Moore, Kristin M. O'Sullivan, Ivna DeSouza, Margaret E. Feeney, Robert L. Eldridge, Erica L. Maier, Daniel E. Kaufmann, Matthew P. Lahaie, Laura Reyor, Giancarlo Tanzi, Mary N. Johnston, Christian Brander, Rika Draenert, Jurgen K. Rockstroh, Heiko Jessen, Eric S. Rosenberg, Simon A. Mallal, and Bruce D. Walker. Selective Escape from CD8+ T-Cell Responses Represents a Major Driving Force of Human Immunodeficiency Virus Type 1 (HIV-1) Sequence Diversity and Reveals Constraints on HIV-1 Evolution. J. Virol., 79(21):13239-13249, Nov 2005. PubMed ID: 16227247. Show all entries for this paper.

Displaying record number 1018

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	vaccine
Experimental methods
Keywords

Vaccine Details

Vaccine type	vaccinia

Notes

This epitope was shown to be processed and presented to appropriate CTL clones upon infection of human target cells with vaccinia virus Ankara (VVA) carrying 20 HIV-1 epitopes recognized by humans.

References

Hanke1998b T. Hanke, T. J. Blanchard, J. Schneider, G. S. Ogg, R. Tan, M. Becker, S. C. Gilbert, A. V. Hill, G. L. Smith, and A. McMichael. Immunogenicities of Intravenous and Intramuscular Administrations of Modified Vaccinia Virus Ankara-Based Multi-CTL Epitope Vaccine for Human Immunodeficiency Virus Type 1 in Mice. J. Gen. Virol., 79:83-90, 1998. PubMed ID: 9460927. Show all entries for this paper.

Hanke1998c T. Hanke, J. Schneider, S. G. Gilbert, A. V. S. Hill, and A. McMichael. DNA Multi-CTL Epitope Vaccines for HIV and Plasmodium falciparum: Immunogenicity in Mice. Vaccine, 16:426-435, 1998. PubMed ID: 9607066. Show all entries for this paper.

Displaying record number 53782

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	(B8)
Immunogen
Experimental methods
Keywords	review, immunodominance, escape, acute/early infection, early-expressed proteins, kinetics, viral fitness and reversion

Notes

This review discusses the importance of 3 factors that impact the selection of immunodominant epitopes in acute HIV infection: i) the kinetics of viral protein expression, ii) the HLA class I background of the infected individual, and iii) the autologous sequence of the infecting virus. This is 1 of 12 peptides listed as immunodominant in acute HIV-1 infection.

References

Lichterfeld2005 Mathias Lichterfeld, Xu G. Yu, Sylvie Le Gall, and Marcus Altfeld. Immunodominance of HIV-1-Specific CD8+ T-Cell Responses in Acute HIV-1 Infection: At the Crossroads of Viral and Host Genetics. Trends Immunol., 26(3):166-171, Mar 2005. PubMed ID: 15745859. Show all entries for this paper.

Displaying record number 54172

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97 HXB2)
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Patient MHC/HLA	PIC1365: A0101, A0201, B0801, B50, Cw0602, Cw0701
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	escape, mutation acquisition, viral fitness and reversion, optimal epitope

Notes

T-cell immunity and the impact of selection were longitudinally studied in a patient from the time of transmission. New epitopes were detected at sites that were shown to be under positive selection. Env was found to be the major target of CTLs and most of the new epitopes were found here. One third of the sites examined were associated with epitope escape mutations from CTL. Acquisition of mutations found at high frequency in the database was suggested to be a result of reversion of CTL epitopes in the absence of immune targeting.
A Nef epitope FLKEeGGL (Nef-94E) presumed escape variant was transmitted from a B8 positive donor to a B8 negative recipient. FLKEgGGL, FLKgeGGL variants as well as FLKEkGGL reversions were found in the recipient subject.

References

Liu2006 Yi Liu, John McNevin, Jianhong Cao, Hong Zhao, Indira Genowati, Kim Wong, Sherry McLaughlin, Matthew D. McSweyn, Kurt Diem, Claire E. Stevens, Janine Maenza, Hongxia He, David C. Nickle, Daniel Shriner, Sarah E. Holte, Ann C. Collier, Lawrence Corey, M. Juliana McElrath, and James I. Mullins. Selection on the Human Immunodeficiency Virus Type 1 Proteome following Primary Infection. J. Virol., 80(19):9519-9529, Oct 2006. PubMed ID: 16973556. Show all entries for this paper.

Displaying record number 54336

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	B8-FL8(Nef)
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	rate of progression, immunodominance, early-expressed proteins

Notes

Immunodominant HIV epitopes in early, primary infection of CTLs were identified and the relative contribution of immune responses restricted to individual HLA class I molecules were studied.
The most frequently recognised epitopes also elicited the greatest CTL response.
HIV-1 Epitope sequence variability was not correlated with immunodominant versus immune sub-dominant responses.
HLA-B*57 and HLA-B*27 restricted responses were the strongest in these early and acute infections - due to dominant responses to a single epitope in each case (TW10 for B*57 and KK10 for B*27).
In the presence of HLA-B*57 and HLA-B*27 restricted responses, the relative contribution of other restricting HLA dropped greatly.

References

Altfeld2006 Marcus Altfeld, Elizabeth T. Kalife, Ying Qi, Hendrik Streeck, Mathias Lichterfeld, Mary N. Johnston, Nicole Burgett, Martha E. Swartz, Amy Yang, Galit Alter, Xu G. Yu, Angela Meier, Juergen K. Rockstroh, Todd M. Allen, Heiko Jessen, Eric S. Rosenberg, Mary Carrington, and Bruce D. Walker. HLA Alleles Associated with Delayed Progression to AIDS Contribute Strongly to the Initial CD8+ T Cell Response against HIV-1. PLoS Med., 3(10):e403, Oct 2006. PubMed ID: 17076553. Show all entries for this paper.

Displaying record number 54804

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	(B8)
Immunogen
Experimental methods
Keywords	review, immunodominance, escape, vaccine antigen design

Notes

This review discusses current literature on particular CTL escape mutations that significantly impair viral fitness and argues for a concerted effort to identify these targets.
This epitope is discussed in the context of the hierarchy of recognized HLA-B8 epitopes during acute infection (recognized by >70% of subjects).

References

Altfeld2006a Marcus Altfeld and Todd M. Allen. Hitting HIV Where It Hurts: An Alternative Approach to HIV Vaccine Design. Trends Immunol., 27(11):504-510, Nov 2006. PubMed ID: 16997629. Show all entries for this paper.

Displaying record number 55499

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay, Tetramer binding
Keywords	characterizing CD8+ T cells

Notes

T-cells were studied for exhaustion and dysfunction in chronic HIV infection. Polyfunctionality of CTL immune response to HIV-1 decreased with persistence of antigen presence over time in chronic infection. CTL exhaustion can thus be halted by reduction in viral antigen load - either by ART or through escape mutations.
PD-1, marker for activation and apoptosis increases over time, but it decreases when epitope mutations develop. CD127 however, is not impacted by viral escape.
163 days after first testing, this epitope, FLKEKGGL, went from dual- and triple-functional to monofunctional in the response it was able to elicit.
Epitope FLKEKGGL showed no variation in a treated patient. 163 and 364 days after first testing, epitope FLKEKGGL showed no variations in untreated patients; 409 days after first testing, epitope FLKEKGGL showed variations in untreated patients to FLrKEGGL, and to FLKEqGGL. Previously published HLA-restriction for FL8 is HLA-B8.

References

Streeck2008 Hendrik Streeck, Zabrina L. Brumme, Michael Anastario, Kristin W. Cohen, Jonathan S. Jolin, Angela Meier, Chanson J. Brumme, Eric S. Rosenberg, Galit Alter, Todd M. Allen, Bruce D. Walker, and Marcus Altfeld. Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1-Specific CD8+ T Cells. PLoS Med, 5(5):e100, 6 May 2008. PubMed ID: 18462013. Show all entries for this paper.

Displaying record number 55657

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ, Chromium-release assay, Intracellular cytokine staining, Proliferation, Tetramer binding
Keywords	TCR usage, characterizing CD8+ T cells

Notes

By studying HIV-1 dysregulation of CTLs at different infection stages induced by inhibitory KIRs (Killer Immunoglobulin-like receptors), it was determined that KIR surface expression on memory T cells correlates with HIV replication. It results in reduced activation, proliferation, cytokine secretion, and killing following TCR stimulation. Since non-TCR-dependent CTL stimulation was unaffected, TCR-mediated stimulation appears to be defective. KIR induced suppression of CTL function was found to be KIR-ligand-independent.
FL8-specific CTLs had heterogeneous surface expression of KIR. Of these tetramer positive B08-CTLs, only KIR- cells were able to secrete IFN-gamma upon stimulation.

References

Alter2008 Galit Alter, Suzannah Rihn, Hendrik Streeck, Nickolas Teigen, Alicja Piechocka-Trocha, Kristin Moss, Kristen Cohen, Angela Meier, Florencia Pereyra, Bruce Walker, and Marcus Altfeld. Ligand-Independent Exhaustion of Killer Immunoglobulin-Like Receptor-Positive CD8+ T Cells in Human Immunodeficiency Virus Type 1 Infection. J. Virol., 82(19):9668-9677, Oct 2008. PubMed ID: 18579582. Show all entries for this paper.

Displaying record number 55848

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Country	Switzerland
Experimental methods	CD8 T-cell Elispot - IFNγ, Intracellular cytokine staining, Other
Keywords	HAART, ART

Notes

By following T-cell function in ART-regimented patients over time, it was shown that ART resulted in reduced viral replication and the restoration of CTLs to polyfunctionality. It is concluded that in vivo antigenic exposure during declining viremia has a positive influence on CTL function.
Epitope FLKEKGGL was used to interrogate CTL function in 37 chronically-infected HIV-1 positive subjects, with respect to cytokine production.

References

Rehr2008 Manuela Rehr, Julia Cahenzli, Anna Haas, David A. Price, Emma Gostick, Milo Huber, Urs Karrer, and Annette Oxenius. Emergence of Polyfunctional CD8+ T Cells after Prolonged Suppression of Human Immunodeficiency Virus Replication by Antiretroviral Therapy. J. Virol., 82(7):3391-404, Apr 2008. PubMed ID: 18199637. Show all entries for this paper.

Displaying record number 1017

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97 IIIB)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords	HAART, ART, responses in children

Notes

Study examines the effect of highly active antiretroviral therapy (HAART) on HIV-1 plasma viral load, CTLp and CTLe frequencies in 8 infected children.
CTLp (precursors) were measured by stimulating in culture and assaying using 51Cr release, against vaccina expressed IIIB Env, Gag, Pol, Nef.
B7-FLKEKGGL tetramer complex was used for one of the children that was HLA-B7, and this infant showed a vigorous response (> 4% of CD8+ T cells) at 9 months of age.
HIV-1 specific CTL responses initially increased in children with complete viral suppression, but then decreased, suggesting viral replication is needed to maintain CTL responses.

References

Spiegel1999 H. M. Spiegel, E. DeFalcon, G. S. Ogg, M. Larsson, T. J. Beadle, P. Tao, A. J. McMichael, N. Bhardwaj, C. O'Callaghan, W. I. Cox, K. Krasinski, H. Pollack, W. Borkowsky, and D. F. Nixon. Changes in Frequency of HIV-1-Specific Cytotoxic T Cell Precursors and Circulating Effectors after Combination Antiretroviral Therapy in Children. J. Infect. Dis., 180:359-368, 1999. PubMed ID: 10395850. Show all entries for this paper.

Displaying record number 57689

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Country	Germany, United States
Experimental methods	Flow cytometric T-cell cytokine assay, Tetramer binding
Keywords	memory cells

Notes

CTL effector-memory differentiation (i.e. presence of CD45RO+/CCR7- or CD45RA+/CCR7- CTL) was studied in relation to 2 surface expression markers, CD45RO+/CCR7- (TemRA) and CD57. HIV-1-specific CTL with TemRA expression form an under-represented population of total TemRA+ CTL; but in subjects with slow progression to disease, a large proportion of their HIV-1-specific CTL are TemRA+. This shows HIV-1-specific CTL differentiation to be TCR-dependent with respect to the marker TemRA. For CD57+ CTL however, maturation was TCR-independent since senescence marker CD57 surface expression was similar for (i) different clonotypes targeting the same HIV-1 epitope (ii) epitope-specific CTL clonotypes at varied stages of differentiation. Thus both TCR-dependent and -independent development of CTL are important for their effector-memory repertoire.
TCRB clonotype distribution between TemRA and TemRO phenotypes of CTL suggest that differentiation is simultaneous from naive CTL to either TemRA or TemRO CTL compartments. This study was conducted on epitope KF11-specific CTL in HLA-B57 subject 10076.
Differentiation into the TemRA memory phenotype was shown to be selective and variable, driven by the selective expansion of distinct TCR clonotype populations within HIV-1-specific CTL populations. FL8-specific- and KK10-specific-memory-CTL in subject 10022 are composed of varying percentages of different TRBV expressions. FL8-specific memory CTL in subject 10071 also express 3 different TRBV genes, resulting in differing proportions of 3 different memory CTL sub-populations.
HLA-B8 restricted CTL specific against epitope FL8 were studied by Tetramer staining and flow cytometry. TemRO, TemRA and memory cells against this epitope were followed.

References

Meyer-Olson2010 Dirk Meyer-Olson, Brenna C. Simons, Joseph A. Conrad, Rita M. Smith, Louise Barnett, Shelly L. Lorey, Coley B. Duncan, Ramesh Ramalingam, and Spyros A. Kalams. Clonal Expansion and TCR-Independent Differentiation Shape the HIV-Specific CD8+ Effector-Memory T-Cell Repertoire In Vivo. Blood, 116(3):396-405, Jul 22 2010. PubMed ID: 20424187. Show all entries for this paper.

Displaying record number 57836

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ, TCR binding
Keywords	rate of progression, TCR usage, optimal epitope

Notes

The study measured the functional avidities of HIV-specific CTL responses targeting 20 optimally defined CTL epitopes in a cohort of 44 HIV controllers and 68 non-controllers. Highest functional avidities were toward HLA-B-restricted epitopes in Gag. Avidities were higher in HIV controllers than non-controllers. Higher-avidity T-cell populations had narrower TCR repertoires.
FLKEKGGL was one of 20 optimal epitopes tested.
CTL response magnitude and functional avidity for this epitope did not change before and after initiation of HAART.

References

Berger2011 Christoph T. Berger, Nicole Frahm, David A. Price, Beatriz Mothe, Musie Ghebremichael, Kari L. Hartman, Leah M. Henry, Jason M. Brenchley, Laura E. Ruff, Vanessa Venturi, Florencia Pereyra, John Sidney, Alessandro Sette, Daniel C. Douek, Bruce D. Walker, Daniel E. Kaufmann, and Christian Brander. High-Functional-Avidity Cytotoxic T Lymphocyte Responses to HLA-B-Restricted Gag-Derived Epitopes Associated with Relative HIV Control. J. Virol., 85(18):9334-9345, Sep 2011. PubMed ID: 21752903. Show all entries for this paper.

Displaying record number 52135

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97 BRU)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords	binding affinity, epitope processing

Notes

Seventy-three 8-11 mer peptides were generated based on putative anchor motifs in the Nef BRU sequence for HLA A2, A3, A24, B7, B8, and B35; these 73 peptides had 81 motifs. 54% bound to the predicted HLA molecule, particularly A2, B7/35, and B8. The strength of HLA-peptide binding was not directly related to the number of individuals that recognized a protein.
20s proteasome cleavage of the Nef protein positions 66-100 showed a large fraction of peptides were cleaved ending at: 87L, 83A, 81Y, 71P, 68F and 67G. The frequency of recognition may be in part dictated by the cleavage step in processing.
FLKEKGGL was recognized in 12/14 (86%) of individuals with HLA B8, and it was a high affinity HLA binder.

References

Choppin2001 Jeannine Choppin, William Cohen, Albert Bianco, Jean-Paul Briand, Francine Connan, Marc Dalod, and Jean-Gérard Guillet. Characteristics of HIV-1 Nef Regions Containing Multiple CD8+ T Cell Epitopes: Wealth of HLA-Binding Motifs and Sensitivity to Proteasome Degradation. J. Immunol., 166(10):6164-6169, 15 May 2001. PubMed ID: 11342637. Show all entries for this paper.

Displaying record number 52312

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FLK
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords	HAART, ART, supervised treatment interruptions (STI)

Notes

Using previously defined epitopes Oxenius2000b,Oxenius2001b in an IFNgamma Elispot assay, 13 chronically HIV-1 infected patients were studied over a period including therapy with standard treatment interruptions (STI).
STIs induced increased recognition of CTL epitopes, but there was no correlation between CTL responses with viral rebound rates, plateau viral loads, or clearance rates.

References

Oxenius2002b Annette Oxenius, Angela R. McLean, Marek Fischer, David A. Price, Sarah J. Dawson, Roland Hafner, Christine Schneider, Helen Joller, Bernard Hirschel, Rodney E. Phillips, Rainer Weber, Huldrych F. Günthard, and Swiss HIV Cohort Study Group. Human Immunodeficiency Virus-Specific CD8+ T-Cell Responses Do Not Predict Viral Growth and Clearance Rates During Structured Intermittent Antiretroviral Therapy. J. Virol., 76(20):10169-10176, Oct 2002. PubMed ID: 12239291. Show all entries for this paper.

Displaying record number 52364

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Patient MHC/HLA	A11, A2, B60, B8, Bw6
Experimental methods
Keywords	HAART, ART

Notes

Four HIV patients with prolonged clinically successful anti-viral therapy but with ongoing evidence of replication and Nef mRNA transcription, showed specific T-cell responses by Elispot and Tetramer staining, maintained for 2-4 years after initiation of HAART.
Nef epitope recognition was detected in all 4 subjects, gp120, Pol and Gag-specific in 1 or 2 subjects -- two patients recognized FLKEKGGL.
The HIV-specific CD8+ T-cells had an intermediate maturation phenotype characterized by low levels of perforin and high levels of CD27 expression.

References

Appay2002 Victor Appay, Pokrath Hansasuta, Julian Sutton, Rachel D. Schrier, Joseph K. Wong, Manohar Furtado, Diane V. Havlir, Steven M. Wolinsky, Andrew J. McMichael, Douglas D. Richman, Sarah L. Rowland-Jones, and Celsa A. Spina. Persistent HIV-1-Specific Cellular Responses Despite Prolonged Therapeutic Viral Suppression. AIDS, 16(2):161-170, 25 Jan 2002. PubMed ID: 11807299. Show all entries for this paper.

Displaying record number 52365

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Patient MHC/HLA	A1, A3, B65, B8, Bw6
Experimental methods
Keywords	HAART, ART

Notes

Four HIV patients with prolonged clinically successful anti-viral therapy but with ongoing evidence of replication and Nef mRNA transcription, showed specific T-cell responses by Elispot and Tetramer staining, maintained for 2-4 years after initiation of HAART.
Nef epitope recognition was detected in all 4 subjects, gp120, Pol and Gag-specific in 1 or 2 subjects -- two patients recognized FLKEKGGL.
The HIV-specific CD8+ T-cells had an intermediate maturation phenotype characterized by low levels of perforin and high levels of CD27 expression.

References

Displaying record number 52438

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	A, B, C, D
Species (MHC/HLA)	human, macaque(B8)
Immunogen	HIV-1 infection, vaccine
Experimental methods
Keywords	subtype comparisons, epitope processing, vaccine-induced immune responses, immunodominance

Vaccine Details

Vaccine type	DNA prime with modified vaccinia Ankara (MVA) boost
Vaccine strain	A clade
Vaccine component	p17 Gag, p24 Gag

Notes

The HIV-1 subtype A focused vaccine HIVA contains p24 and p17, in a reversed order relative to the Gag polyprotein to prevent myristylation of p17, which could direct the protein to the cell membrane and inhibit efficient peptide processing and class I presentation, as well as a polyepitope string of conserved, often immunodominant epitopes that were selected to have particularly good cross-reactive potential for the A-clade epidemic in Nairobi, Kenya. A DNA and MVA prime-boost vaccination protocol using the HIVA antigen will be used in a phase III clinical trial in Kenya. This epitope is included in the polyepitope string Hanke2000.
Multiple CD4+ or CD8+ T-cell vaccine-induced responses to peptide pools were detected using intracellular cytokine staining and IFNgamma Elispot assays after vaccination of 5 macaques. The response to the Mamu A*01 SIV p27 epitope p11C (CTPYDINQM), included in the polyepitope region, was not immunodominant in the Mamu A*01 vaccinated macaques, possibly because of processing limitations in context of the artificial polyepitope string Wee2002.

References

Hanke2000 Tomas Hanke and Andrew J. McMichael. Design and construction of an experimental HIV-1 vaccine for a year-2000 clinical trial in Kenya. Nat. Med., 6(9):951-955, Sep 2000. PubMed ID: 10973301. Show all entries for this paper.

Wee2002 Edmund G.-T. Wee, Sandip Patel, Andrew J. McMichael, and Tomáš Hanke. A DNA/MVA-Based Candidate Human Immunodeficiency Virus Vaccine for Kenya Induces Multi-Specific T Cell Responses in Rhesus Macaques. J. Gen. Virol., 83(Pt 1):75-80, Jan 2002. PubMed ID: 11752703. Show all entries for this paper.

Displaying record number 52646

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Patient MHC/HLA	A1, A3, B62, B8, Cw3, Cw7
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	binding affinity, acute/early infection, early-expressed proteins

Notes

CTL epitope responses were mapped in 21 men within 15-92 days post-HIV-1 infection. Subjects initially a showed narrow immune responses with a mean of 2.3 epitopes recognized per patient. The immune response broadened later in infection. No correlation between the plasma viral load and the number of recognized epitopes or the frequency of IFN-gamma secreting cells was observed, and there was no correlation between the functional avidity of a responses and the abundance of IFN-secreting cells that recognized the epitope. The first epitopes to be recognized tended not to be the most avid, and earliest responses tended to be directed against Nef, Tat, Vpr, and Env.
All HIV-1 proteins except Vpu were recognized, and a responses to a total of 41 optimal epitopes were characterized; 24 had been identified previously. 48% of the total T-cell responses were directed against Nef and 43% were directed against Gag.
More common HLA alleles were less frequently used in primary infection than less common alleles, for example A3, B35, B57, and B62 were more frequently recognized than A1, A2, A30, and A44.

References

Cao2003 Jianhong Cao, John McNevin, Sarah Holte, Lisa Fink, Lawrence Corey, and M. Juliana McElrath. Comprehensive Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon-Secreting CD8+ T Cells in Primary HIV-1 Infection. J. Virol., 77(12):6867-6878, Jun 2003. PubMed ID: 12768006. Show all entries for this paper.

Displaying record number 52966

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(87-95)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Patient MHC/HLA	A28, A3, B7, B8
Experimental methods	Chromium-release assay, Flow cytometric T-cell cytokine assay, Proliferation
Keywords	HAART, ART, memory cells

Notes

HAART restores HIV specific immunity after advanced infection by increase of CD4+ and CD8+ T cell numbers after suppression of viral replication. However, HIV specific CTLs emerged only with detectable viral replication breakthroughs and were short-lived while CD4+ T-cell responses remained compromised, suggesting failure of generating stable CD8+ memory T-cells in the absence of HIV-specific T-helper responses.

References

Gamberg2004 Jane Gamberg, Lisa Barrett, Ian Bowmer, Constance Howley, and Michael Grant. Immune Reconstitution and Viral Stimulation Are Required to Restore HIV-Specific CD8 T Cell Responses Following Advanced Infection. J. Clin. Immunol., 24(2):115-124, Mar 2004. PubMed ID: 15024178. Show all entries for this paper.

Displaying record number 57933

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Patient MHC/HLA	A0101, A0301, B0801, B3503, Cw0401, Cw0701
Country	United States
Experimental methods	CD8 T-cell Elispot - IFNγ
Keywords	acute/early infection

Notes

The study tracked changes in amino acid residues across the whole genome over time during the first year of infection in 11 individuals representing 4 donor-recipient pairs and 3 independent seroconverters. 9 of the 11 individuals were enrolled during acute infection. In most cases, a single founder virus underwent selection, primarily in env and nef. Mutations were detected in the first week, and became consensus as early as 21 days post-onset of symptoms. Putative escape mutations were often rapidly replaced with mutually-exclusive mutations nearby. Escape mutations were more frequent than reversions.
Previously-documented B8-restricted epitope FLKEKGGL was recognized by EliSpot assay in 1 HIV-positive B8-positive patient. The patient was negative at day 7, and positive by day 127 post-seroconversion.

References

Herbeck2011 Joshua T. Herbeck, Morgane Rolland, Yi Liu, Sherry McLaughlin, John McNevin, Hong Zhao, Kim Wong, Julia N. Stoddard, Dana Raugi, Stephanie Sorensen, Indira Genowati, Brian Birditt, Angela McKay, Kurt Diem, Brandon S. Maust, Wenjie Deng, Ann C. Collier, Joanne D. Stekler, M. Juliana McElrath, and James I. Mullins. Demographic Processes Affect HIV-1 Evolution in Primary Infection before the Onset of Selective Processes. J. Virol., 85(15):7523-7534, Aug 2011. PubMed ID: 21593162. Show all entries for this paper.

Displaying record number 1020

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords

Notes

CTL specific responses were measured over a 1.3 to 1.5 year period in members of the Sydney Blood Bank Cohort (SBBC) who had been infected with a natural attenuated strain of HIV-1 which was Nef-defective.
Some of these patients had prolonged high levels of CTL effector and memory cells despite low viral load.

References

Dyer1999 W. B. Dyer, G. S. Ogg, M. A. Demoitie, X. Jin, A. F. Geczy, S. L. Rowland-Jones, A. J. McMichael, D. F. Nixon, and J. S. Sullivan. Strong Human Immunodeficiency Virus (HIV)-Specific Cytotoxic T-Lymphocyte Activity in Sydney Blood Bank Cohort Patients Infected with nef-Defective HIV Type 1. J. Virol., 73:436-443, 1999. PubMed ID: 9847349. Show all entries for this paper.

Displaying record number 1300

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef( SF2)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FL8
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords

Notes

This peptide elicited a weak CTL response during acute HIV-1 infection in patient PI004.
Three CTL responses, to epitopes TSTLQEQIGW, ISPRTLNAW, and KAFSPEVIPMF, were evident early after infection; CTL responses to SLYNTVATL, QASQEVKNW, EIYKRWII, and FLKEKGGL were detectable at 5 months post-infection and beyond.
FL8 was recognized in an additional patient, AC29, in chronic infection.

References

Goulder2001 P. J. Goulder, M. M. Addo, M. A. Altfeld, E. S. Rosenberg, Y. Tang, U. Govender, N. Mngqundaniso, K. Annamalai, T. U. Vogel, M. Hammond, M. Bunce, H. M. Coovadia, and B. D. Walker. Rapid Definition of Five Novel HLA-A*3002-Restricted Human Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Epitopes by Elispot and Intracellular Cytokine Staining Assays. J. Virol., 75(3):1339-1347, Feb 2001. URL: http://jvi.asm.org/cgi/content/full/75/3/1339. PubMed ID: 11152507. Show all entries for this paper.

Displaying record number 1366

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(92-99)
Epitope	`FLKEKGGL`	Epitope Alignment
Epitope Name	FLK
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords	HAART, ART

Notes

Characterization of specific CTL phenotype patterns in response to variation of the virus load in response to antiviral therapy in 3 patients with chronic HIV-1 infection.
CTL activation in response to increasing viral load sequential, and co-segregated with apoptosis only during later stages of the response, suggesting antigen-specific cell-death is restricted to distinct CTL sub-populations.

References

Oxenius2001b A. Oxenius, H. F. Gunthard, B. Hirschel, S. Fidler, J. N. Weber, P. J. Easterbrook, J. I. Bell, R. E. Phillips, and D. A. Price. Direct ex vivo analysis reveals distinct phenotypic patterns of HIV-specific CD8(+) T lymphocyte activation in response to therapeutic manipulation of virus load. Eur. J. Immunol., 31(4):1115-21, Apr 2001. PubMed ID: 11298336. Show all entries for this paper.

Displaying record number 1375

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(92-99)
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	FLK
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords	HAART, ART, supervised treatment interruptions (STI), immunodominance, escape, acute/early infection

Notes

Patients who started therapy at acute HIV-1 infection (three with sustained therapy, two with limited therapy upon early infection) had strong HIV specific CD4 proliferative responses and were able to maintain a CTL response even with undetectable viral load -- three patients that had delayed initiation of HAART had no HIV specific CD4 proliferative responses and lost their CTL responses when HAART was eventually given and their viral loads became undetectable.
Six of the 7/8 study subjects that were HLA B8 recognized this early dominant CTL epitope.
Patient SC2 (HLA A1, B7/8, Cw0701/0702, DR4/53, DQ7) had CTL responsiveness against epitopes FLKEKGGL, GPKVKQWPL, and GEIYKRWII peptides -- FLKEKGGL tetramer staining steadily declined and at day 1340 the FLKEKGGL stained cells were no longer detected and the escape mutant FLKENGGI was found in 8/10 clones.
Patient SC9 (HLA A1/2, B8/13, Cw0/0701, DR2/11, DQ6/7) had a CTL response against epitopes FLKEKGGL, ILKEPVHGV, SQRRQDILDLWIYHTQGYFPDWQNY, and GEIYKRWII peptides and all responses declined during therapy initiated at day 390 but were restored when therapy become intermittent.
Patient SC19(HLA A11/12, B8/44, Cw06/0701, DR3/7, DR52/53, DQ 2/8) had a CTL response to epitopes FLKEKGGL, GEIYKRWII, ACQGVGGPGHK, AVDLSHFLK, and FNCGGEFFY that declined during therapy initiated at day 197.
Patient SC10(HLA A1/3, B8/35, DR1/8, DQ 4/5) had sustained therapy started during acute infection and maintained an immunodominant response to FLKEKGGL and a response to GEIYKRWII through day 1088.
Patient SC12(HLA A1, B8/39, Cw0701/0702, DR2/3, DR51/52, DQ2/6) had sustained therapy started during acute infection and maintained an immunodominant response to FLKEKGGL throughout and minor responses to GEIYKRWII, DCKTILKAL, GGKKKYKLK -- GEIYKRWII and GGKKKYKLK responses were stimulated by a brief period off therapy.
Patient SC11(HLA A1, B8, Cw0201, DR3/11, DR52, DQ2/7) started therapy early, remained on therapy for 40 days, then reinitiated HAART at day 640 had a CTL response to FLKEKGGL, GPKVKQWPL, and GEIYKRWII throughout and received a benefit from the early limited course therapy.

References

Oxenius2000b A. Oxenius, D. A. Price, P. J. Easterbrook, C. A. O'Callaghan, A. D. Kelleher, J. A. Whelan, G. Sontag, A. K. Sewell, and R. E. Phillips. Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes. Proc. Natl. Acad. Sci. U.S.A., 97(7):3382-7, 28 Mar 2000. URL: http://www.pnas.org/cgi/content/full/97/7/3382. PubMed ID: 10737796. Show all entries for this paper.

Displaying record number 1409

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords

Notes

HLA tetramers to six epitopes were used to study HLA-A2, B8 and B57 CTL in 54 patients -- HIV-specific tetramer positive cells were inversely correlated with viral load in patients with high CD4, but in patients with CD4 T-cells below 400 high tetramer frequencies were found despite high viral load.
Most patients have high levels of HIV-specific T-cell expansions, but many of these cells aren't functional.
In 15 of the patients, the proportion of IFN gamma producing tetramer cells correlated with AIDS-free survival.
Stimulation with HLA-B8 p24 and Nef epitopes significantly increased Nef-specific T-cell numbers in 2 patients (748 and 1113)
There were more functional IFN-gamma producing Nef-specific T-cells within the T-cell population than there were active p24 Gag-specific T-cells.
No correlation between elevated numbers of Nef-specific CTL cells and plasma viral load was observed.

References

Kostense2001 S. Kostense, G. S. Ogg, E. H. Manting, G. Gillespie, J. Joling, K. Vandenberghe, E. Z. Veenhof, D. van Baarle, S. Jurriaans, M. R. Klein, and F. Miedema. High viral burden in the presence of major HIV-specific CD8(+) T cell expansions: evidence for impaired CTL effector function. Eur. J. Immunol., 31(3):677-86, Mar 2001. PubMed ID: 11241270. Show all entries for this paper.

Displaying record number 1421

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(88-95)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords

Notes

One of the 51 HIV-1 epitopes selected by Ferrari et al. as good candidate CTL epitopes for vaccines by virtue of being conserved and presented by common HLA alleles.

References

Ferrari2000 G. Ferrari, D. D. Kostyu, J. Cox, D. V. Dawson, J. Flores, K. J. Weinhold, and S. Osmanov. Identification of highly conserved and broadly cross-reactive HIV type 1 cytotoxic T lymphocyte epitopes as candidate immunogens for inclusion in Mycobacterium bovis BCG-vectored HIV vaccines. AIDS Res. Hum. Retroviruses, 16(14):1433-43, 20 Sep 2000. PubMed ID: 11018863. Show all entries for this paper.

Displaying record number 1578

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(88-95 SF2)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords	HAART, ART, acute/early infection

Notes

Therapy provided during acute infection resulted in a narrower CTL response, stronger T help response, and a less diverse viral population than was seen in individuals treated during chronic infection.
The breadth and specificity of the response was determined using ELISPOT by studying 19 individuals with pre-seroconversion therapy (Group 1), 11 individuals with primary infection but post-seroconversion therapy (Group 2), and 10 individuals who responded to HAART given during chronic infection (Group 3), using 259 overlapping peptides spanning p17, p24, RT, gp41, gp120 and Nef.
Previously described and newly defined optimal epitopes were tested for CTL response.
Number of HLA-B8+ individuals that had a CTL response to this epitope broken down by group: 3/3 group 1, 1/3 group 2, and 1/2 group 3.

References

Altfeld2001b M. Altfeld, E. S. Rosenberg, R. Shankarappa, J. S. Mukherjee, F. M. Hecht, R. L. Eldridge, M. M. Addo, S. H. Poon, M. N. Phillips, G. K. Robbins, P. E. Sax, S. Boswell, J. O. Kahn, C. Brander, P. J. Goulder, J. A. Levy, J. I. Mullins, and B. D. Walker. Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J. Exp. Med., 193(2):169-80, 15 Jan 2001. URL: http://www.jem.org/cgi/content/full/193/2/169. PubMed ID: 11148221. Show all entries for this paper.

Displaying record number 1705

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(89-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords

Notes

Combined tetramer and intracellular cytokine staining was used to study the function of circulating CD8+ T cells specific for HIV and CMV.
HIV-specific CD8+ T cells expressed lower levels of perforin than CMV-specific CD8+ T cells from the same donor, and this was associated with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation.
In most donors, between 50% and 95% of the activated virus-specific CD8+ T cells produced IFN-γ and MIP-1β with a distinct subset that failed to produce TNF-α

References

Appay2000 V. Appay, D. F. Nixon, S. M. Donahoe, G. M. Gillespie, T. Dong, A. King, G. S. Ogg, H. M. Spiegel, C. Conlon, C. A. Spina, D. V. Havlir, D. D. Richman, A. Waters, P. Easterbrook, A. J. McMichael, and S. L. Rowland-Jones. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med., 192(1):63-75, 3 Jul 2000. URL: http://www.jem.org/cgi/content/full/192/1/63. PubMed ID: 10880527. Show all entries for this paper.

Displaying record number 1825

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords

Notes

Tetramer assays were compared with three functional assays in 42 people with chronic HIV infection: ELISPOT, intracellular cytokine staining, and precursor frequency (limiting dilution assay [LDA])
HIV-specific tetramer staining CTLs appeared to be active, and inert CTL were not found to play a significant role in chronic pediatric or adult HIV infection.

References

Goulder2000b P. J. Goulder, Y. Tang, C. Brander, M. R. Betts, M. Altfeld, K. Annamalai, A. Trocha, S. He, E. S. Rosenberg, G. Ogg, C. A. O'Callaghan, S. A. Kalams, R. E. McKinney, Jr., K. Mayer, R. A. Koup, S. I. Pelton, S. K. Burchett, K. McIntosh, and B. D. Walker. Functionally inert HIV-specific cytotoxic T lymphocytes do not play a major role in chronically infected adults and children. J. Exp. Med., 192(12):1819-32, 18 Dec 2000. URL: http://www.jem.org/cgi/content/full/192/12/1819. PubMed ID: 11120778. Show all entries for this paper.

Displaying record number 1019

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(88-95)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human(B8)
Immunogen	HIV-1 infection
Experimental methods
Keywords

Notes

Natural variants for this epitope have been observed in several donors.
Substitutions Q5, N5, E5 that alter anchor position 5 are not well recognized.
Substitution I2 binds well to B8 and is recognized.

References

Goulder1997c P. J. R. Goulder, S. W. Reid, D. A. Price, C. A. O'Callaghan, A. J. McMichael, R. E. Phillips, and E. Y. Jones. Combined Structural and Immunological Refinement of HIV-1 HLA-B8 Restricted Cytotoxic T Lymphocyte Epitopes. Eur. J. Immunol., 27:1515-1521, 1997. PubMed ID: 9209505. Show all entries for this paper.

Displaying record number 1014

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(89-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human
Immunogen	HIV-1 infection
Experimental methods
Keywords	immunodominance

Notes

Only 4/11 HLA-A2+ HIV+ individuals had CTL that reacted to SLYNTVATL, calling into question whether it is immunodominant.
95 optimally-defined peptides from this database were used to screen for INFγ responses to other epitopes.
1/11 of the A2+ individuals that responded to SLYNTVATL reacted with seven other epitopes including this epitope previously described as presented by B8.

References

Betts2000 M. R. Betts, J. P. Casazza, B. A. Patterson, S. Waldrop, W. Trigona, T.-M Fu, F. Kern, L. J. Picker, and R. A. Koup. Putative Immunodominant Human Imunodeficiency Virus-Specific CD8+ T Cell Responses Cannot Be Predicted by Major Histocompatibility Complex Class I Haplotype. J. Virol., 74:9144-9151, 2000. PubMed ID: 10982361. Show all entries for this paper.

Displaying record number 54684

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef(90-97)
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human
Immunogen	HIV-1 infection
Patient MHC/HLA	A1, B7, B8
Experimental methods	CD8 T-cell Elispot - IFNγ, HLA binding
Keywords	HAART, ART, escape, viral fitness and reversion

Notes

In order to reconcile apparent conflicts between a CTL-protective role as suggested by HLA-1 alleles associated with different rates of progression to AIDS, and a CTL non-protective role as suggested by the fact that virus clearance following ART is not impaired in advanced AIDS, a model is made that quantifies the efficiency of HIV-1-specific CTLs in vivo. As a surrogate for the actual rate of CTL-killing of infected cells, the model rests on calculating virus escape rate for an epitope and subtracting its reversion rate upon transmission to a non-restricting HLA bearing host. It is shown that CTLs recognizing a single epitope kill only 2% of productively infected CD4+ cells. The rate of CTL lysis was found to be significantly faster during primary infection than in chronic infection. However, the authors suggest that small differences in CTL lysis rate can translate into large differences in terms of absolute numbers of infected cells killed, which are likely to be clinically relevant.
The best estimate of escape rate for this epitope, FLKEKGGL, was found to be 0.049/day, with SE of 0.012.
In the subject studied, a number of variants arose in the Nef epitope 90-97 (including complete epitope deletion) that were poorly recognized by CTL or escaped recognition completely.

References

Asquith2006 Becca Asquith, Charles T. T. Edwards, Marc Lipsitch, and Angela R. McLean. Inefficient Cytotoxic T Lymphocyte-Mediated Killing of HIV-1-Infected Cells In Vivo. PLoS Biol., 4(4):e90, Apr 2006. PubMed ID: 16515366. Show all entries for this paper.

Displaying record number 59394

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
Subtype	B
Species (MHC/HLA)	human
Immunogen	HIV-1 infection
Patient MHC/HLA	LTNP/EC-20: A02, B08, B49, Cw07
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	rate of progression, immunodominance

Notes

The study compared B*27/*57-positive versus negative patients among a cohort of long-term nonprogressors and elite controllers with B*27/B*57-negative progressors. Overlapping 15-mers that elicited responses in multiple patients, or were among the strongest responses in a single patient, were narrowed down by truncation to define optimal epitopes, 11 of which were novel.
FLKEKGGL was recognized by 3/5 LTNP/EC, and 2/3 had it as a dominant response. The restricting HLA (B*08) was predicted, not confirmed experimentally.

References

Migueles2015 Stephen A. Migueles, Daniel Mendoza, Matthew G. Zimmerman, Kelly M. Martins, Sushila A. Toulmin, Elizabeth P. Kelly, Bennett A. Peterson, Sarah A. Johnson, Eric Galson, Kate O. Poropatich, Andy Patamawenu, Hiromi Imamichi, Alexander Ober, Catherine A. Rehm, Sara Jones, Claire W. Hallahan, Dean A. Follmann, and Mark Connors. CD8+ T-Cell Cytotoxic Capacity Associated with Human Immunodeficiency Virus-1 Control Can Be Mediated through Various Epitopes and Human Leukocyte Antigen Types. EBioMedicine, 2(1):46-58, Jan 2015. PubMed ID: 26137533. Show all entries for this paper.

Displaying record number 55095

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human
Immunogen	HIV-1 infection
Experimental methods	CD8 T-cell Elispot - IFNγ, Intracellular cytokine staining, Other
Keywords	binding affinity, acute/early infection

Notes

Differences in early versus chronic AIDS include a decline in CTL number accompanied by a reducing viremia. Comparative analysis of such CTLs in this study show that early infection is characterized by a different clonotypic composition and higher functional avidity of CTLs followed by their selective depletion during transition to chronic disease. The total magnitude of CTL cytokine production is lower in early infection. Intraindividual, early CTLs' functional avidity for the same epitope decreases concomitantly with a reduction in clonotypic TCR repertoire especially of strongly activated and CD127lo, CD38+, Ki-67hi CTLs while progressing to chronic infection states.
None of the target epitopes, including this epitope FLKEKGGL seen in 4 patinents, underwent sequence changes.

References

Lichterfeld2007 Mathias Lichterfeld, Xu G. Yu, Stanley K. Mui, Katie L. Williams, Alicja Trocha, Mark A. Brockman, Rachel L. Allgaier, Michael T. Waring, Tomohiko Koibuchi, Mary N. Johnston, Daniel Cohen, Todd M. Allen, Eric S. Rosenberg, Bruce D. Walker, and Marcus Altfeld. Selective Depletion of High-Avidity Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ T Cells after Early HIV-1 Infection. J. Virol., 81(8):4199-4214, Apr 2007. PubMed ID: 17287271. Show all entries for this paper.

Displaying record number 54939

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human
Immunogen	HIV-1 infection, vaccine
Patient MHC/HLA	A1, A10 (26); B17 (57), B8
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	vaccine-induced immune responses

Vaccine Details

Vaccine type	canarypox
Vaccine strain	B clade LAI, B clade MN
Vaccine component	Gag-Pol, gp120, gp41

Notes

T cell responses during early infection in individuals previously enrolled in HIV vaccine trials were compared with those of nonvaccinated subjects.
None of the breakthrough infections possessed vaccine-induced T-cell responses preinfection and 85-86% of vaccinees and nonvaccinees with primary infection developed T-cell responses postinfection, indicating that vaccinees' ability to mount T-cell response postinfection is not compromized by previous immunization.
Breakthrough subjects recognized 43 T-cell epitopes, 8 of them novel, and 25% were present in the vaccine.
This epitope was not contained in the vaccine, the vaccinated patient recognized it after infection.

References

Horton2006a Helen Horton, Colin Havenar-Daughton, Deborah Lee, Erin Moore, Jianhong Cao, John McNevin, Thomas Andrus, Haiying Zhu, Abbe Rubin, Tuofu Zhu, Connie Celum, and M. Juliana McElrath. Induction of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses in HIV Vaccine Trial Participants Who Subsequently Acquire HIV-1 Infection. J. Virol., 80(19):9779-9788, Oct 2006. PubMed ID: 16973582. Show all entries for this paper.

Displaying record number 60507

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location	Nef
Epitope	`FLKEKGGL`	Epitope Alignment
		Show epitope variants
Epitope Name	B8-FL8
Species (MHC/HLA)	human
Immunogen	HIV-1 infection
Patient MHC/HLA	ACS 19957: A01, A02, B0801, B15; ACS 19885: A01, A02, B0801, B27; ACS 19861: A01, A02, B0801, B51; ACS 19453: A01, A02, B0801, B38; ACS 19342: A01, A02, B0801, B40; ACS 18840: A02, B0801, B27; ACS 18839: A0207, B0801, B27; ACS 18785: A01, A02, B07, B0801
Country	Netherlands
Experimental methods	Other, Tetramer binding
Keywords	TCR usage

Notes

Eight asymptomatic, chronic HIV-1-infected, ART-naive, HLA-A*02+, B*08+ subjects from the Amsterdam cohort were interrogated at two time points for correlations between HIV-1 epitope mutation, antigen-specific T-cell expansion i.e. TCR diversity, and repertoire of responding CTL clonotypes. Data suggest continuous bidirectional adaptation between HIV-1 and HIV-specific T-cell clonotypes at the TCR-antigenic epitope interface.
Viral epitope variation has no direct correlation with CTL repertoire and diversity, though parallel evolution of TCR repertoire, virus and CTL response was noted, independent of individual subjects. Different patterns of TCRβ evolution were observed in subjects who showed delayed progression to disease.
Epitope B8-FL8, FLKEKGGL, was at 100% wild type sequence only in subject 3 at time point 1 (t₁). Variants were FLKEtGGL, FLKErGGL, FLKEmGGL, FLKEeGGL, FLnEKGGL, lLnEKGGL, and FLrEKGGL.

References

Costa2015 Ana I. Costa, Dan Koning, Kristin Ladell, James E. McLaren, Bart P. X. Grady, Ingrid M. M. Schellens, Petra van Ham, Monique Nijhuis, José A. M. Borghans, Can Keşmir, David A. Price, and Debbie van Baarle. Complex T-Cell Receptor Repertoire Dynamics Underlie the CD8+ T-Cell Response to HIV-1. J. Virol., 89(1):110-119, Jan 2015. PubMed ID: 25320304. Show all entries for this paper.

Displaying record number 54913

HXB2 Location	Nef(90-97) DNA(9064..9087)	Nef Epitope Map
Author Location
Epitope	`FLKEKGGL`	Epitope Alignment
Species (MHC/HLA)	human
Immunogen	HIV-1 infection
Patient MHC/HLA	A0101; B0801, B*1401
Experimental methods	CD8 T-cell Elispot - IFNγ, Flow cytometric T-cell cytokine assay
Keywords	vaccine-induced immune responses

Notes

T cell responses during early infection in individuals previously enrolled in HIV vaccine trials were compared with those of nonvaccinated subjects.
None of the breakthrough infections possessed vaccine-induced T-cell responses preinfection and 85-86% of vaccinees and nonvaccinees with primary infection developed T-cell responses postinfection, indicating that vaccinees' ability to mount T-cell response postinfection is not compromized by previous immunization.
Breakthrough subjects recognized 43 T-cell epitopes, 8 of them novel, and 25% were present in the vaccine.
FLKEKGGL was recognized by a placebo patient after infection.