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The Characterization of HIV-1 Specific CD4+ T Helper Epitopes

Lisa A. Cosimi and Eric S. Rosenberg

Massachusetts General Hospital, Boston, MA 02114, lcosimi@partners.org

Introduction

There is increasing evidence that CD4+ T helper cells play a critical role in the maintenance of virus-specific immunity in most chronic viral infections (Matloubian, Battegay, van Herrrath, Walter). Unfortunately, in the majority of HIV-1 infected individuals, these cellular responses are functionally impaired in all stages of disease (Wahren, Berzofsky, Krowka, Pontesilli, Schrier, Rosenberg). The most notable exception to this > observation is that the robust T helper cell responses are observed in persons with long-term non-progressive infection (Rosenberg). Furthermore, in studies of untreated chronic HIV-1 infection, virus-specific T helper cell responses are inversely correlated with plasma HIV-1 viremia suggesting that these cells provide an important role in viral control (Rosenberg, Kalams). Recently, significant advances have been made in determining the functional relevance of these CD4+ T helper cell responses. For example, several reports from the SIV macaque model indicate that virus-specific T helper cell responses are essential for viral control when therapy is discontinued (Barouch, Hel, Lifson, Lori). The functional relevance of HIV-1 specific T helper cell responses has been further defined by human treatment interruption studies (Lisziewicz, Rosenberg). Finally, vaccine studies have shown that Th1 help is required for a successful cytolytic T lymphocyte (CTL) response (Gahery-Segard, Mortara).

Despite mounting evidence that HIV-specific T helper cells play a critical role in the immune response against HIV-1, little is actually known about the precise epitopes targeted by these cells. A successful immunotherapeutic strategy is likely to require successful induction of HIV-1 specific antibody, CD8+ CTL and CD4+ T helper responses. The identification of a repertoire of dominant HIV-1 specific T helper epitopes that can bind to the most common HLA alleles in the population will be critical to this process (Bangham). The purpose of this review is to provide an overview of those best-characterized human HIV-1 specific T helper cell epitope regions that have been described to date in natural infection.

Characteristics of T helper epitopes

CD4+ T cells are stimulated by peptides presented in association with Major Histocompatibility Complex (MHC) class~II. The peptides are derived mainly from exogenous proteins that have undergone proteolytic degradation and processing within the endocytic pathway of antigen presenting cells (APCs) (reviewed in Watts and Geuze). In brief, these antigens bind to APCs and are internalized via intracellular vesicles in which they undergo proteolytic degradation in preparation for loading onto MHC class~II molecules. The alpha and beta chains of these molecules are simultaneously synthesized and dimerized within the endoplasmic reticulum (ER) with the C-terminal domains forming the peptide-binding groove. These alpha-beta heterodimers then associate with a membrane glycoprotein, termed the invariant chain (Ii), whose lumenal domain, class~II-associated Ii peptide (CLIP) functions to block the peptide-binding groove from any class~I peptides within the ER (Roche). This complex is transported to endosomes and delivered to the endocytic pathway to associate with the peptides processed from exogenous antigen. As opposed to class~I molecules, the class~II binding groove is open and thereby able to accommodate longer peptides of 13--18 amino acids. The majority of identified class~II associated peptides have been of this length, although a crystallization model (Reinherz) suggests that a central core of as few as 9 amino acids actually come into contact with the T cell receptor. Confirmation of this report is provided by recent published data (Malhotra) and Norris et al . (personal communication) that identify HIV-1 specific T helper epitopes of 9 amino acids in length. Peptides that bind to class~II molecules lack conserved anchor residues at the ends of the peptide. Rather, class~II molecules and their associated peptide interact via hydrogen bonding along the length of the central peptide (Madden). In general, this sequence is composed of an aromatic or hydrophobic residue at the amino terminus and three additional hydrophobic residues in the central portion and at the carboxyl-terminus. Elution of peptides from class~II molecules has shown that over 30 have a proline residue at position two and a cluster of prolines at the carboxyl terminal end (Jardetsky).

Methods for measuring T helper responses

Historically, several in vitro assays have been used to detect T helper responses in HIV-1 infection. To date, however, there has been no agreed upon standard methodology for the utilization of these assays or for the minimum responses required to be considered significant. The measurement of cytokine secretion in the supernatant of antigen stimulated cells was the method predominantly used initially. Subsequently, the Lymphocyte Proliferation Assay (LPA), measuring [3H] thymidine incorporation in counts per minute (CPM) by antigen stimulated cells has been more commonly used. Results are reported as either CPM, delta counts per minute (DCPM: the CPM in the stimulated sample minus the CPM in the negative control), or Stimulation Index (SI: the mean CPM in the stimulated sample divided by the mean CPM in the negative control). This assay is attractive because in vitro proliferation is presumed to be correlated with in vivo function. However, methodology with regards to incubation time, concentration of stimulating antigen and cutoffs for minimum SI or DCPM signifying a positive response have varied between studies.

Most recently, newer assays have been utilized which measure cytokine secretion with high sensitivity. The Elispot assay measures cytokine secreted by a single cell though without CD8 depletion it is not immediately able to differentiate between T helper and CTL responses. Further specificity is provided by Intracellular Cytokine Staining (ICS) which quantifies, by flow cytometric gating of CD4 cells, cytokine production by this cell population. As opposed to all of the prior methods it has the immediate advantage of being CD4+ specific. Despite the potentially increased sensitivity of these assays for identifying T helper responses, the correlation with functional capacity remains to be elucidated.

HIV-1 specific T helper epitopes

Multiple laboratories have contributed to the identification of HIV-1 specific T helper epitopes. Although few epitopes have been fully characterized and fine mapped in natural infection, there are multiple promising epitopic regions that have been studied in murine, non-human primate and vaccine models in non-HIV infected individuals. All of these are listed within the LANL Molecular Immunology Database.

The following table includes the identified human epitope regions that have been characterized in natural infection. It is likely that these regions will be further specified to provide HLA restricted epitopes that may be useful in future immunotherapeutic strategies. In some cases we have included examples where several groups have identified overlapping regions. We anticipate that as these epitopes are further characterized and the minimum or optimal sequences are identified some of these regions may well include multiple epitopes while others may be removed from the list. We have also made note of the methods used to detect the responses and the variation in the assay when applicable. In some cases we have omitted epitopes where the exact sequence was not recorded though these may well prove to be significant epitopes when further defined.

We anticipate that as CD4 epitopes are more specifically delineated in the future more stringent criteria will be adopted and the list will be adapted accordingly to include those epitopes that are likely to be most useful in development of immunotherapeutic strategies. For this list to be most useful, included epitopes should ideally meet the following criteria: 1. A T helper cell response detected in natural infection via LPA, Elispot or ICS. Verification through CD8+ depletion, clonal analysis or flow cytometry should be performed for all cases. Ideally lymphoproliferation assay SI should be greater than 5 and/or DCPM> 600. Further study into the correlation between the various assays is still needed. 2. Truncation data with demonstration of the minimal stimulatory epitope. 3. HLA restriction.

 

Table 1 HIV-1 specific T helper epitopes that have been characterized in natural infection

Protein

AA

HLA

Sequence

SL:

Cytokine

N

Reference

2-5

>5

p17 21--35 DR13.02 LRPGGKKKYKLKHIV

X

  IL-2 NA Harcourt98
  33--47 ND HIVWASRELERFAVN

X

  NT 9/16 Wahren89
  93--107 ND EIKDTKAEALDKIEEE

X

  NT 4/16 Wahren89
  118--132 ND AAADTGHSSQVSQNY

X

  NT 4/16 Wahren89
p24 1--11 DR1 PIVQNLQGQMV

X

  IL-2 NA Harcourt98
  1--15 ND PIVQNLQGQMVHQAI  

X

NT 10/16 Wahren89
  1--22 ND PIVQNIQGQMVHQAISPRTLNA  

X

IFN- U 1/2 LTNP Rosenberg97
  31--52 ND AFSPEVIPMFSALSEGATPQDL  

X

IFN- U 2/2 LTNP Rosenberg97
  48--62 ND TPQDLNTMLTVGGH  

X

NT 8/19 Adams97
  76--85 ND EAAEWDRVHP  

X

NT 11/24 Adams97
  76--90 ND EAAEWDRVHVHAGP

X

  NT 6/16 Wahren89
  81--102 ND DRVHPVHAGPIAPGQMREPRGS  

X

IFN- U 1/2 LTNP Rosenberg97
  96--110 ND MREPRGSKIAGTTST

X

  NT 6/16 Wahren89
  111--132 ND LQEQIGWMTNNPPIPVGEIYKR  

X

IFN- U 2/2 LTNP Rosenberg97
  119--138 DRB1*1302 TNNPPIPVGEIYKRWIILGL  

X

IFN- NA Malhotra01
  128--137 DRB1*1302 EIYKRWIILG  

X

IFN- NA Malhotra01
  131--152 ND KRWIILGLNKIVRMYSPTSILD     IFN- U 2/2 LTNP Rosenberg97
  135--154 ND ILGLNKIVRMYSPTSILDIR  

X

NT 8/24 Adams97
  146--160 ND SPTSILDIRQGPKEP

X

  NT 8/16 Wahren89
  156--170 ND GPKEPFRDYVDRFYK

X

  NT 8/16 Wahren89
  156--174 ND QPKEPFRDYVDRFYKTLRA  

X

NT 5/21 Adams97
  163--177 DRB1*1302 DYVDRFYKTLRAEQA  

X

IFN- NA Malhotra01
p15 30--44 ND FNCGKEFHTARNCRA

X

  NT 5/16 Wahren89
  55--69 ND KEGHQMKDCTERQAN

X

  NT 5/16 Wahren89
  60--74 ND MKDCTERQANFLGKI

X

  NT 6/16 Wahren89
  98--112 ND ESFRSGVETTTPPQK

X

  NT 8/16 Wahren89
RT 36--52 ND EICTEMEKEGKISKIGP

NT

NT

IL-2 9/17 Degroot91
vpr 66--80 ND QLLFIHFRIGCRHSR

X

  NT 6/16 Sarobe94
rev 9--23 ND DEELIRTVRLIKLLY

X

  IL-10 NA Blazevic95
  25--39 ND SNPPPNPEGTRQARR

X

  IL-10 NA Blazevic95
  33--48 ND GTRQARRNRRRRWRER

X

  IL-10 NA Blazevic95
  41--56 ND RRRRWRERQRQIHSIS

X

  IL-10 NA Blazevic95
gp160 37--47 ND VYYVPVWKEA  

X

NT 8/17 Nehete98
  105--117 ND HEDIISLWDQSLK

NT

NT

IL-2 4/35 Clerici89
  112--141 ND WDQSLKPCVKLTPLCVSLKCTDLGNATNTN  

X V

NT 11/36 Sitz99
  147--168 ND MMMEKGEIKNCSFNISTSIRGK  

X V

NT 19/36 Sitz99
  185--215 ND NDTTSYTLTSCNTSVITQACPKVSFEPIPI  

X V

NT 11/36 Sitz99
  199--211 ND SVITQACSKVSFE

X

  NT NA Nehete98
  264--287 ND SLAEEEVVIRSANFTDNAKTIIVQ  

X V

NT 18/36 Sitz99
  269--283 ND EVVIRSANFTDNAKT

X

  NT 6/20 Wahren89
  274--288 ND SANFTDNAKTIIVQL

X

  NT 8/20 Wahren89
  308--322 ND RIQRGPGRAFVTIGK     IL-2 1/22 Clerici89
  309--323 ND EQRGPGRAFYVTIGKI

X

  NT 6/20 Wahren89
  314--328 ND GRAFVTIGKIGNMRQ

X

  NT 7/20 Wahren89
  314--341 ND GRAFVTIGKIGNMRQAHCNISRAKWNAT  

X V

NT 10/36 Sitz99
  332--354 ND NISRAKWNATLKQIASKLRREQFG  

X V

NT 11/36 Sitz99
  364--378 ND SSGGKPEIVTHSFNC

X

  NT 8/20 Wahren89
  369--383 ND PEIVTHSFNCGGEFF

X

  NT 8/20 Wahren89
  394--408 ND TWFNSTWSTKGSNNT

X

  NT 11/20 Wahren89
  418--436 ND CRIKQIINMWQGVGGKAMYA

X

  NT NA Nehete98
  422--437 ND KQIINMWQEVGKAMYA

NT

NT

IL-2 4/35 Clerici89
  438--460 ND PISGQIRCSSNITGLLLTRDGGN  

X V

  14/36 Sitz99
  459--473 ND GNSNNESEIFRPGGG

X

  NT 9/20 Wahren89
  476--490 ND DMRDNWRSELYKYKV

X

  NT 8/20 Wahren89
  484--498 ND YKYKVVKIEPLGVAP

X

  NT 8/20 Wahren89
  519--543 ND FLGFLGAAGSTMGAASLTLTVQARC

X

  NT NA Nehete98
  547--561 ND GIVQQQNNLLRAIEA  

X

NT 3/23 Wahren89
  562--576 ND QQHLLQLTVWGIKQL

X

  NT 9/23 Wahren89
  586--597 ND YLRDQQLLGIWG

X

  NT NA Nehete98
  593--604 ND LGIWGCSGKLIC

X

  NT NA Bell92
  647--664 ND EESQNQQEKNEKNEQELL

X

  NT 6/23 Wahren89
  667--681 ND ASLWNWFNITNWLWY

X

  NT 11/23 Wahren89
  682--696 ND IKLFIMIVGGLVGLR  

X

NT 6/23 Wahren89
  827--841 ND DRVIEVVQGAYRAIR         Clerici89
  842--856 ND HIPRRIRQGLERILL

X

  NT 9/23 Wahren89

 

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last modified: Tue Nov 23 10:11 2010


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