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polyclonal VC20013: Based on the results of Malherbe2014 [PMID: 25210191], this study selected immunogens from envs emerging during early stages of neutralization breadth (within the first 2 years of infection) in 2 clade B-infected human subjects, VC20013 and VC20014. Coimmunizing rhesus macaques with HIV-1 gp160 DNA and gp140 trimeric protein selected from these envs induced polyclonal nAbs against tier 2 autologous viruses. The IgG polyclonal responses in macaques emulated the targeting to specific regions of Env known to be associated with autologous and heterologous neutralizing Abs developed in the 2 human subjects. Over time, macaque polyclonal IgG responses showed increasing binding affinity and tier 1 heterologous neutralization. The study observed correlations between tier 2 autologous neutralization and tier 1 heterologous neutralization, as well as overall breadth. The activation of Env-specific follicular helper CD4 T cells in lymphocytes isolated from inguinal lymph nodes of vaccinated macaques also correlated with tier 2 autologous neutralization. These results demonstrate the potential for native Env derived from subjects at the time of neutralization broadening as effective HIV vaccine elements.
Hessell2016a
(vaccine antigen design, vaccine-induced immune responses, polyclonal antibodies)
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VC20013: The polyclonal response of human subjects VC20013 and VC10014 demonstrated increasing neutralization breadth against a panel of HIV-1 isolates over time. Full-length functional env genes were cloned longitudinally from these subjects from months after infection through 2.6 to 5.8 years of infection. Motifs associated with the development of breadth in published, cross-sectional studies were found in the viral sequences of both subjects. To test the immunogenicity of envelope vaccines derived from time points obtained during and after broadening of neutralization activity within these subjects, rabbits were coimmunized 4 times with selected multiple gp160 DNAs and gp140-trimeric envelope proteins. In an assay of rabbit polyclonal responses, the most rapid and persistent neutralization of multiclade tier 1 viruses was elicited by envelopes that were circulating in plasma at time points prior to the development of 50% neutralization breadth in both human subjects. The breadth elicited in rabbits was not improved by exposure to later envelope variants. Env immunogen sequences were tested for binding to a panel of well studied mAbs of various binding types (VRC01, HJ16, b12, b6, PG9, PGT121, 2G12, 2F5, F240); all gp140s bound to weak or non-neutralizing antibodies b6 and F240. MAb b6 also bound BG505 SOSIP, while F240 did not, suggesting that cluster I gp41 epitopes, which become exposed during gp120 shedding, are more easily accessed on these trimers than on BG505-SOSIP. These data have implications for vaccine development in describing a target time point to identify optimal env immunogens.
Malherbe2014
(vaccine antigen design, vaccine-induced immune responses, polyclonal antibodies)
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VC20013: This study details the isolation and characterization of a panel of human monoclonal antibodies (mAbs) from two subjects who developed broadly neutralizing autologous antibody responses during HIV-1 infection. Neutralizing antibodies (NAbs) isolated from these subjects mapped mostly to epitopes in the Env V3 loop region and the CD4 binding site. Despite the broad neutralizing activity in the polyclonal sera, none of the individual neutralizing mAbs isolated from either subject exhibited the cumulative breadth of neutralization present in the serum of the subjects.
Chukwuma2018
(autologous responses, neutralization, broad neutralizer)
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Two HIV-1-infected individuals, VC10014 and VC20013, were monitored from early infection until well after they had developed broadly neutralizing activity. The bNAb activity developed about 1 year after infection and mapped to a single epitope in both subjects. Isolates from each subject, taken at five different time points, were tested against monoclonal bNAbs: VRC01, B12, 2G12, PG9, PG16, 4E10, and 2F5. In subject VC10014, the bNAb activity developed around 1 year postinfection and targeted an epitope that overlaps the CD4-BS and is similar to (but distinct from) bNAb HJ16. In the case of VC20013, the bNAb activity targeted a novel epitope in the MPER that is critically dependent on residue 677 (mutation K677N).
Sather2014
(antibody binding site, neutralization, broad neutralizer, polyclonal antibodies)
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The breadth of plasma neutralizing Ab responses correlated with the time since infection, plasma viremia levels, and the binding avidity of anti-Env Abs. Abs to the V1 and V2 regions did not contribute to the cross-neutralizing activity of plasmas examined, while abs to the V3 region were effective only against certain primary isolates. Broad and potent cross-NAb responses were shown to be due to the presence of CD4BS Abs, however, the presence of these Abs did not guarantee broad neutralizing activity of plasma. It was shown that plasma samples collected from same subject only months apart could neutralize different HIV isolates, or same isolates but with different potencies, suggesting changes in both the titers and Ab specificities over short periods of time. Several plasmas were identified that exhibited broad breadth, neutralizing over 75% of the isolates tested (e.g., VC10014 and VC20013). One patient (VC10042) was identified with plasma (collected two decades after infection) that displayed extremely broad breadth, neutralizing all isolates tested.
Sather2009
(neutralization, variant cross-reactivity, polyclonal antibodies)
References
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5 references.
Isolation Paper
Sather2009
D. Noah Sather, Jakob Armann, Lance K. Ching, Angeliki Mavrantoni, George Sellhorn, Zachary Caldwell, Xuesong Yu, Blake Wood, Steve Self, Spyros Kalams, and Leonidas Stamatatos. Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection. J. Virol., 83(2):757-769, Jan 2009. PubMed ID: 18987148.
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Chukwuma2018
Valentine U. Chukwuma, Nurgun Kose, D. Noah Sather, Gopal Sapparapu, Rachel Falk, Hannah King, Vidisha Singh, Rebecca Lampley, Delphine C. Malherbe, Noah T. Ditto, Jonathan T. Sullivan, Trevor Barnes, Benjamin J. Doranz, Celia C. Labranche, David C. Montefiori, Spyros A. Kalams, Nancy L. Haigwood, and James E. Crowe, Jr. Increased Breadth of HIV-1 Neutralization Achieved by Diverse Antibody Clones Each with Limited Neutralization Breadth. PLoS One, 13(12):e0209437, 2018. PubMed ID: 30566528.
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Hessell2016a
Ann J. Hessell, Delphine C. Malherbe, Franco Pissani, Sean McBurney, Shelly J. Krebs, Michelle Gomes, Shilpi Pandey, William F. Sutton, Benjamin J. Burwitz, Matthew Gray, Harlan Robins, Byung S. Park, Jonah B. Sacha, Celia C. LaBranche, Deborah H. Fuller, David C. Montefiori, Leonidas Stamatatos, D. Noah Sather, and Nancy L. Haigwood. Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens. J. Immunol., 196(7):3064-3078, 1 Apr 2016. PubMed ID: 26944928.
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Malherbe2014
Delphine C. Malherbe, Franco Pissani, D. Noah Sather, Biwei Guo, Shilpi Pandey, William F. Sutton, Andrew B. Stuart, Harlan Robins, Byung Park, Shelly J. Krebs, Jason T. Schuman, Spyros Kalams, Ann J. Hessell, and Nancy L. Haigwood. Envelope variants circulating as initial neutralization breadth developed in two HIV-infected subjects stimulate multiclade neutralizing antibodies in rabbits. J Virol, 88(22):12949-67 doi, Nov 2014. PubMed ID: 25210191
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Sather2014
D. Noah Sather, Sara Carbonetti, Delphine C. Malherbe, Franco Pissani, Andrew B. Stuart, Ann J. Hessell, Mathew D. Gray, Iliyana Mikell, Spyros A. Kalams, Nancy L. Haigwood, and Leonidas Stamatatos. Emergence of Broadly Neutralizing Antibodies and Viral Coevolution in Two Subjects during the Early Stages of Infection with Human Immunodeficiency Virus Type 1. J. Virol., 88(22):12968-12981, Nov 2014. PubMed ID: 25122781.
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