HIV-1 infection begins with the fusion of viral and target cell membranes, which is mediated by the viral envelope glycoprotein upon engagement with host cellular receptors. The HIV-1 envelope glycoprotein undergoes large structural rearrangements during viral entry. There are at least three distinct conformational states of the HIV-1 envelope protein: the prefusion, prehairpin intermediate, and postfusion conformations. Each conformation presents distinct antigenic surfaces to the immune system. In this proposal, we seek to assess the impact of HIV-1 envelope conformation on immunogenicity. We hypothesize that different functional conformers of the HIV-1 envelope protein elicit distinct profiles of antibody responses. A deeper understanding of the relationship between HIV-1 envelope structure and immunogenicity will likely facilitate future structure-based immunogen design strategies at a level of sophistication and structural detail that has not previously been possible. To explore this hypothesis, we propose the following three Specific Aims: 1. We will assess the immunogenicity of the three principal conformational states of gp41 corresponding to the prefusion, prehairpin intermediate, and postfusion conformations in guinea pigs; 2. We will investigate the immunogenicity of uncleaved, precursor state (gp140)3 trimers and cleaved (gp120/gp41ecto)3 trimer complexes in guinea pigs;and 3. We will determine the immunogenicity and protective efficacy of the optimal HIV-1 envelope immunogens in rhesus monkeys.

Public Health Relevance

An HIV-1 envelope immunogen with the ability to induce broadly reactive NAbs will likely be an essential component for any successful AIDS vaccine. Given the recent disappointing results from the Merck rAd5 vaccine trials aimed at eliciting T cell responses, the need to identify envelope immunogens that can elicit broadly reactive neutralizing antibodies has never been greater. In this proposal, we will assess the impact of HIV-1 envelope conformation on the profile of elicited neutralizing antibody responses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-SV-A (M2))
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Pensiero, Michael N
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Beth Israel Deaconess Medical Center
United States
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Stephenson, Kathryn E; Neubauer, George H; Reimer, Ulf et al. (2015) Quantification of the epitope diversity of HIV-1-specific binding antibodies by peptide microarrays for global HIV-1 vaccine development. J Immunol Methods 416:105-23
Barouch, Dan H; Picker, Louis J (2014) Novel vaccine vectors for HIV-1. Nat Rev Microbiol 12:765-71
Barouch, Dan H; Michael, Nelson L (2014) Accelerating HIV-1 Vaccine Efficacy Trials. Cell 159:969-72
Nkolola, Joseph P; Bricault, Christine A; Cheung, Ann et al. (2014) Characterization and immunogenicity of a novel mosaic M HIV-1 gp140 trimer. J Virol 88:9538-52
Whitney, James B; Hill, Alison L; Sanisetty, Srisowmya et al. (2014) Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys. Nature 512:74-7
Chen, Jia; Frey, Gary; Peng, Hanqin et al. (2014) Mechanism of HIV-1 neutralization by antibodies targeting a membrane-proximal region of gp41. J Virol 88:1249-58
Barouch, Dan H; Deeks, Steven G (2014) Immunologic strategies for HIV-1 remission and eradication. Science 345:169-74
Nkolola, Joseph P; Cheung, Ann; Perry, James R et al. (2014) Comparison of multiple adjuvants on the stability and immunogenicity of a clade C HIV-1 gp140 trimer. Vaccine 32:2109-16
Li, Hualin; Stephenson, Kathryn E; Kang, Zi Han et al. (2014) Common features of mucosal and peripheral antibody responses elicited by candidate HIV-1 vaccines in rhesus monkeys. J Virol 88:13510-5
Barouch, Dan H; Stephenson, Kathryn E; Borducchi, Erica N et al. (2013) Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell 155:531-9

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