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)
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Scripps Research Institute
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Tsui, Carlson; Martinez-Martin, Nuria; Gaya, Mauro et al. (2018) Protein Kinase C-? Dictates B Cell Fate by Regulating Mitochondrial Remodeling, Metabolic Reprogramming, and Heme Biosynthesis. Immunity 48:1144-1159.e5
Porichis, Filippos; Hart, Meghan G; Massa, Alexandra et al. (2018) Immune Checkpoint Blockade Restores HIV-Specific CD4 T Cell Help for NK Cells. J Immunol 201:971-981
Cao, Liwei; Diedrich, Jolene K; Ma, Yuanhui et al. (2018) Global site-specific analysis of glycoprotein N-glycan processing. Nat Protoc 13:1196-1212
Cheng, Hao D; Grimm, Sebastian K; Gilman, Morgan Sa et al. (2018) Fine epitope signature of antibody neutralization breadth at the HIV-1 envelope CD4-binding site. JCI Insight 3:
Sarkar, Anita; Bale, Shridhar; Behrens, Anna-Janina et al. (2018) Structure of a cleavage-independent HIV Env recapitulates the glycoprotein architecture of the native cleaved trimer. Nat Commun 9:1956
Harvey, David J; Seabright, Gemma E; Vasiljevic, Snezana et al. (2018) Isomer Information from Ion Mobility Separation of High-Mannose Glycan Fragments. J Am Soc Mass Spectrom 29:972-988
Leipold, Michael D; Obermoser, Gerlinde; Fenwick, Craig et al. (2018) Comparison of CyTOF assays across sites: Results of a six-center pilot study. J Immunol Methods 453:37-43
Cohen, Yehuda Z; Lorenzi, Julio C C; Seaman, Michael S et al. (2018) Neutralizing Activity of Broadly Neutralizing Anti-HIV-1 Antibodies against Clade B Clinical Isolates Produced in Peripheral Blood Mononuclear Cells. J Virol 92:
Gaya, Mauro; Barral, Patricia; Burbage, Marianne et al. (2018) Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells. Cell 172:517-533.e20
Tsui, Carlson; Maldonado, Paula; Montaner, Beatriz et al. (2018) Dynamic reorganisation of intermediate filaments coordinates early B-cell activation. Life Sci Alliance 1:e201800060

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