Non-human Primate Immunogenicity Studies of HIV-1 immunogens

Mascola, John

Abstract

The genetic diversity of HIV-1 envelope glycoproteins (Env) remains a major obstacle to the development of an antibody-based AIDS vaccine. In prior studies, we examined the breadth and magnitude of neutralizing antibody (NAb) responses in rhesus monkeys after immunization with DNA prime-recombinant adenovirus (rAd) boost vaccines encoding either single or multiple genetically distant Env immunogens. Using a standardized multi-tier panel of reference Env pseudoviruses for NAb assessment, we showed that monkeys immunized with a mixture of Env immunogens (clades A, B, and C) exhibited a greater breadth of NAb activity against neutralization sensitive Tier 1 viruses following both vaccination and challenge compared to monkeys immunized with a single Env immunogen (clade B or C). However, all groups of Env-vaccinated monkeys demonstrated only limited neutralizing activity against Tier 2 pseudoviruses, which are more characteristic of the neutralization sensitivity of circulating HIV-1. Additional immunogenicity studies are evaluating vectors with new Env inserts and various forms of soluble Env proteins.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIAAI005011-09
• Application #: 8148415
• Support Year: 9
• Fiscal Year: 2010
• Total Cost: $332,967

Institution

• Name: National Institute of Allergy and Infectious Diseases

Publications

Flatz, Lukas; Cheng, Cheng; Wang, Lingshu et al. (2012) Gene-based vaccination with a mismatched envelope protects against simian immunodeficiency virus infection in nonhuman primates. J Virol 86:7760-70

Sundling, Christopher; Li, Yuxing; Huynh, Nick et al. (2012) High-resolution definition of vaccine-elicited B cell responses against the HIV primary receptor binding site. Sci Transl Med 4:142ra96

Yeh, Wendy W; Brassard, Laura M; Miller, Caroline A et al. (2012) Envelope variable region 4 is the first target of neutralizing antibodies in early simian immunodeficiency virus mac251 infection of rhesus monkeys. J Virol 86:7052-9

Santra, Sampa; Muldoon, Mark; Watson, Sydeaka et al. (2012) Breadth of cellular and humoral immune responses elicited in rhesus monkeys by multi-valent mosaic and consensus immunogens. Virology 428:121-7

George, Jeffy; Cofano, Egidio Brocca; Lybarger, Elizabeth et al. (2011) Early short-term antiretroviral therapy is associated with a reduced prevalence of CD8(+)FoxP3(+) T cells in simian immunodeficiency virus-infected controller rhesus macaques. AIDS Res Hum Retroviruses 27:763-75

Sun, Yue; Asmal, Mohammed; Lane, Sophie et al. (2011) Antibody-dependent cell-mediated cytotoxicity in simian immunodeficiency virus-infected rhesus monkeys. J Virol 85:6906-12

Asmal, Mohammed; Sun, Yue; Lane, Sophie et al. (2011) Antibody-dependent cell-mediated viral inhibition emerges after simian immunodeficiency virus SIVmac251 infection of rhesus monkeys coincident with gp140-binding antibodies and is effective against neutralization-resistant viruses. J Virol 85:5465-75

Whitney, James B; Hraber, Peter T; Luedemann, Corinne et al. (2011) Genital tract sequestration of SIV following acute infection. PLoS Pathog 7:e1001293

Letvin, Norman L; Rao, Srinivas S; Montefiori, David C et al. (2011) Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys. Sci Transl Med 3:81ra36

Yeh, Wendy W; Rao, Srinivas S; Lim, So-Yon et al. (2011) The TRIM5 gene modulates penile mucosal acquisition of simian immunodeficiency virus in rhesus monkeys. J Virol 85:10389-98