The overall mission of this CHAVI-ID application is to define immunogens and immunization regimens that induce sustained HIV cross-protective B cell and CD4+ T cell responses in preclinical models and, thereby, guide product development strategies for a preventive human AIDS vaccine. For Focus #2, our hypothesis is that long-term humoral immunity is critically dependent on CD4+ T cells, and particularly T follicular helper (Tfh) cells, and that the efficient generation of these cells is an essential and obligatory component of an effective HIV vaccine. Nearly all licensed anti-viral vaccines induce neutralizing antibodies and the development of such antibodies is typically CD4+ T cell dependent. Therefore understanding and controlling CD4+ T cells, and Tfh cells in particular, is important for rational vaccine strategies. Focus #2 is designed to improve our knowledge of: 1) the specificity, phenotype and function of Tfh cells in HIV infection and in humans who have received licensed successful vaccines;2) the pathways involved that lead to the induction of Tfh cells;3) the precise Tfh signals that lead to the induction of affinity maturation and broadly neutralizing HIV antibodies;and 4) the role of HIV-specific effector CD4+ T cells in the early focal control of mucosal HIV infection. Tfh cells are also potentially extremely useful biomarkers in human vaccine clinical trials as predictors of long-term humoral immunity and antibody quality. The information gained in Focus #2 will be translated into the design of immunogens and immunization strategies in Focus #1 for evaluation in knock-in mice and NHPs. As we gather together information on optimal immunogens and immunization strategies, we will move forward with small-scale human trials with the advice and close involvement of our Vaccine Discovery Scientific Research Support Component.
An HIV vaccine is urgently needed. A long-term antibody response is the central attribute of most successful human vaccines, and 24 of the 26 licensed human vaccines almost certainly protect primarily on the basis of neutralizing antibody responses. The development of virtually all neutralizing antibodies is CD4+ T cell dependent. Therefore, understanding and controlling CD4+ T cells is important for developing true rational vaccine development strategies.
|Sok, Devin; Doores, Katie J; Briney, Bryan et al. (2014) Promiscuous glycan site recognition by antibodies to the high-mannose patch of gp120 broadens neutralization of HIV. Sci Transl Med 6:236ra63|
|Murin, Charles D; Julien, Jean-Philippe; Sok, Devin et al. (2014) Structure of 2G12 Fab2 in complex with soluble and fully glycosylated HIV-1 Env by negative-stain single-particle electron microscopy. J Virol 88:10177-88|
|Scharf, Louise; Scheid, Johannes F; Lee, Jeong Hyun et al. (2014) Antibody 8ANC195 reveals a site of broad vulnerability on the HIV-1 envelope spike. Cell Rep 7:785-95|
|Doria-Rose, Nicole A; Schramm, Chaim A; Gorman, Jason et al. (2014) Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies. Nature 509:55-62|
|Tong, Tommy; Crooks, Ema T; Osawa, Keiko et al. (2014) Multi-parameter exploration of HIV-1 virus-like particles as neutralizing antibody immunogens in guinea pigs, rabbits and macaques. Virology 456-457:55-69|
|Li, Shuzhao; Rouphael, Nadine; Duraisingham, Sai et al. (2014) Molecular signatures of antibody responses derived from a systems biology study of five human vaccines. Nat Immunol 15:195-204|
|Gitlin, Alexander D; Shulman, Ziv; Nussenzweig, Michel C (2014) Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature 509:637-40|
|Pulendran, Bali (2014) Systems vaccinology: probing humanity's diverse immune systems with vaccines. Proc Natl Acad Sci U S A 111:12300-6|
|Bates, John T; Keefer, Christopher J; Slaughter, James C et al. (2014) Escape from neutralization by the respiratory syncytial virus-specific neutralizing monoclonal antibody palivizumab is driven by changes in on-rate of binding to the fusion protein. Virology 454-455:139-44|
|Sundling, Christopher; Zhang, Zhenhai; Phad, Ganesh E et al. (2014) Single-cell and deep sequencing of IgG-switched macaque B cells reveal a diverse Ig repertoire following immunization. J Immunol 192:3637-44|
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