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. New antigens, structure based design of known neutralizing epitopes, are being evaluated.

  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 #
1ZIAAI005011-12
Application #
8745607
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2013
Total Cost
$330,804
Indirect Cost

  Institution

Name
National Institute of Allergy and Infectious Diseases
Department
Type
DUNS #
City
State
Country
Zip Code

  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

Showing the most recent 10 out of 21 publications