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.
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.
|Barouch, Dan H; Ghneim, Khader; Bosche, William J et al. (2016) Rapid Inflammasome Activation following Mucosal SIV Infection of Rhesus Monkeys. Cell 165:656-67|
|Dev, Jyoti; Park, Donghyun; Fu, Qingshan et al. (2016) Structural basis for membrane anchoring of HIV-1 envelope spike. Science 353:172-5|
|Stephenson, Kathryn E; Neubauer, George H; Bricault, Christine A et al. (2016) Antibody Responses After Analytic Treatment Interruption in Human Immunodeficiency Virus-1-Infected Individuals on Early Initiated Antiretroviral Therapy. Open Forum Infect Dis 3:ofw100|
|Abbink, Peter; Maxfield, Lori F; Ng'ang'a, David et al. (2015) Construction and evaluation of novel rhesus monkey adenovirus vaccine vectors. J Virol 89:1512-22|
|Chen, Jia; Kovacs, James M; Peng, Hanqin et al. (2015) HIV-1 ENVELOPE. Effect of the cytoplasmic domain on antigenic characteristics of HIV-1 envelope glycoprotein. Science 349:191-5|
|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|
|Maxfield, Lori F; Abbink, Peter; Stephenson, Kathryn E et al. (2015) Attenuation of Replication-Competent Adenovirus Serotype 26 Vaccines by Vectorization. Clin Vaccine Immunol 22:1166-75|
|Alter, Galit; Barouch, Dan H (2015) Natural evolution of broadly neutralizing antibodies. Cell 161:427-8|
|Barouch, Dan H; Alter, Galit; Broge, Thomas et al. (2015) Protective efficacy of adenovirus/protein vaccines against SIV challenges in rhesus monkeys. Science 349:320-4|
|Bricault, Christine A; Kovacs, James M; Nkolola, Joseph P et al. (2015) A multivalent clade C HIV-1 Env trimer cocktail elicits a higher magnitude of neutralizing antibodies than any individual component. J Virol 89:2507-19|
Showing the most recent 10 out of 34 publications