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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project with Complex Structure Cooperative Agreement (UM1)
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Special Emphasis Panel (ZAI1-JBS-A (M1))
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Scripps Research Institute
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Pauthner, Matthias; Havenar-Daughton, Colin; Sok, Devin et al. (2017) Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches. Immunity 46:1073-1088.e6
Mayer, Christian T; Gazumyan, Anna; Kara, Ervin E et al. (2017) The microanatomic segregation of selection by apoptosis in the germinal center. Science 358:
Richard, Jonathan; Prévost, Jérémie; von Bredow, Benjamin et al. (2017) BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity. J Virol 91:
Andrabi, Raiees; Su, Ching-Yao; Liang, Chi-Hui et al. (2017) Glycans Function as Anchors for Antibodies and Help Drive HIV Broadly Neutralizing Antibody Development. Immunity 47:1004
Sok, Devin; Le, Khoa M; Vadnais, Melissa et al. (2017) Rapid elicitation of broadly neutralizing antibodies to HIV by immunization in cows. Nature 548:108-111
Polonskaya, Zinaida; Deng, Shenglou; Sarkar, Anita et al. (2017) T cells control the generation of nanomolar-affinity anti-glycan antibodies. J Clin Invest 127:1491-1504
Zeltina, Antra; Krumm, Stefanie A; Sahin, Mehmet et al. (2017) Convergent immunological solutions to Argentine hemorrhagic fever virus neutralization. Proc Natl Acad Sci U S A 114:7031-7036
Baxter, Amy E; Niessl, Julia; Fromentin, Rémi et al. (2017) Multiparametric characterization of rare HIV-infected cells using an RNA-flow FISH technique. Nat Protoc 12:2029-2049
Guenaga, Javier; Garces, Fernando; de Val, Natalia et al. (2017) Glycine Substitution at Helix-to-Coil Transitions Facilitates the Structural Determination of a Stabilized Subtype C HIV Envelope Glycoprotein. Immunity 46:792-803.e3
Bale, Shridhar; Goebrecht, Geraldine; Stano, Armando et al. (2017) Covalent Linkage of HIV-1 Trimers to Synthetic Liposomes Elicits Improved B Cell and Antibody Responses. J Virol 91:

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