The central hypotheses of this CHAVI-ID application are that a successful HIV vaccine should elicit protective antibodies (Abs), and that the combination of B cell and CD4+ T ceil responses is critical for the induction and long-term maintenance of vaccine protection. The overall mission of the 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. We propose to develop an HIV vaccine based on a deep understanding of the critical attributes of immune responses that provide protection against AIDS viruses, through two focused and highly integrated efforts. Focus #1 will concentrate on B cell and antibody research to guide the development of immunogens that elicit protective HIV antibody responses in appropriate animal models. Focus #2 will concentrate on CD4+ T cell research, taking advantage of key preliminary data to maximize the T cell help offered to B cell responses through immunization, and to harness the direct antiviral activity of CD4+ T cells. We argue that this combined approach will lead to the discovery of novel immunogens and immunization strategies that will generate measurable cross-protective antibody responses. We will then build on such advances iteratively, by improving the most promising constructs and protocols until vaccine protection is achieved. A critical component of our proposal is the strength of our research team in immunology, virology and structural biology. The Director, Dennis Burton, has made major contributions to understanding broad antibody neutralization of HIV and antibody protection in animal models of HIV infection. The Scientific Leadership Group (SLG) members are Rati Ahmed, Michel Nussenzweig, Bruce Walker and Ian Wilson, who have made crucial advances in describing the structure and function of antibodies against HIV and the induction and maintenance of B and T cell immunity to the virus. The team will be sustained by five Scientific Research Support Components (SRSCs), including strong Operations and Management, that have been assembled to maximally accelerate progress toward the designated goals.
With 33 million infected individuals worldwide, an HIV vaccine is urgently needed to slow and eventually eliminate new infections. This proposal seeks to discover immunogens and immunization strategies that induce antibody and cellular immune responses that, in concert, are able to protect against exposure to the enormous diversity of global HIV isolates.
|Scheid, Johannes F; Horwitz, Joshua A; Bar-On, Yotam et al. (2016) HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature 535:556-60|
|Barton, John P; Goonetilleke, Nilu; Butler, Thomas C et al. (2016) Relative rate and location of intra-host HIV evolution to evade cellular immunity are predictable. Nat Commun 7:11660|
|Briney, Bryan; Sok, Devin; Jardine, Joseph G et al. (2016) Tailored Immunogens Direct Affinity Maturation toward HIV Neutralizing Antibodies. Cell 166:1459-1470.e11|
|Landais, Elise; Huang, Xiayu; Havenar-Daughton, Colin et al. (2016) Broadly Neutralizing Antibody Responses in a Large Longitudinal Sub-Saharan HIV Primary Infection Cohort. PLoS Pathog 12:e1005369|
|van Gils, Marit J; van den Kerkhof, Tom L G M; Ozorowski, Gabriel et al. (2016) An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability. Nat Microbiol 2:16199|
|Moldt, Brian; Le, Khoa; Carnathan, Diane G et al. (2016) Neutralizing antibody affords comparable protection against vaginal and rectal SHIV challenge in macaques. AIDS :|
|Lu, Ching-Lan; Murakowski, Dariusz K; Bournazos, Stylianos et al. (2016) Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 352:1001-4|
|Tam, Hok Hei; Melo, Mariane B; Kang, Myungsun et al. (2016) Sustained antigen availability during germinal center initiation enhances antibody responses to vaccination. Proc Natl Acad Sci U S A 113:E6639-E6648|
|Havenar-Daughton, Colin; Carnathan, Diane G; Torrents de la PeÃ±a, Alba et al. (2016) Direct Probing of Germinal Center Responses Reveals Immunological Features and Bottlenecks for Neutralizing Antibody Responses to HIV Env Trimer. Cell Rep 17:2195-2209|
|Dan, Jennifer M; Lindestam Arlehamn, Cecilia S; Weiskopf, Daniela et al. (2016) A Cytokine-Independent Approach To Identify Antigen-Specific Human Germinal Center T Follicular Helper Cells and Rare Antigen-Specific CD4+ T Cells in Blood. J Immunol 197:983-93|
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