Design of immunogens capable of inducing neutralizing antibodies (NtAb) against diverse isolates of human immunodeficiency virus (HIV) remains an unmet goal in AIDS vaccines research. Multiple factors may contribute to the difficulty in generating broadly NtAb against HIV. These include conformational masking of the conserved epitopes around the receptor and coreceptor binding sites (bs), as well as occlusion by glycan moieties ("glycan shield"). We recently demonstrated that removal of an N-linked glycan in the C-terminal stem of the V2 loop of HIV-1 gp120 resulted in increased neutralizing sensitivity to CD4bs antibodies and the ability of the mutant Env to mediate CD4-independent infection. Immunization with this mutant Env resulted in cross-reactive NtAb responses in macaques. Based on these findings, we hypothesize that: (1) changes resulting from specific glycan modifications lead to increased stability or accessibility of conserved epitopes in the receptor/coreceptor bs;(2) greater accessibility of these conserved sites enhances their function as targets for cross-reactive NtAb responses. In this project, we propose to test these hypotheses by examining the correlation between specific glycan modifications, receptor/coreceptor binding properties and the ability of the modified Env to induce cross-reactive NtAb and to project against SHIV challenge in macaques.
Specific Aims : 1. To determine the effect of specific N-linked glycan modifications on Env antigenicity, functional integrity, receptor/coreceptor usage, and immunogenity 2. To compare the immunogenicity of native and modified Env from macrophage-tropic R5 viruses that exhibit differential affinity for CD4 and sensitivity to CD4bs antibodies (from Project 1) 3. To examine the effect of glycan modifications on a panel of Env that show enhanced ability to induce cross-reactive NtAb responses (from Project 2) 4. To examine the protective efficacy of modified Env immunogens in macaque challenge models Results from these studies are likely to provide further insight for the design of immunogens capable of eliciting NtAb against diverse isolates of HIV-1.
|Suschak, John J; Wang, Shixia; Fitzgerald, Katherine A et al. (2015) Identification of Aim2 as a sensor for DNA vaccines. J Immunol 194:630-6|
|Pouliot, Kimberly; Buglione-Corbett, Rachel; Marty-Roix, Robyn et al. (2014) Contribution of TLR4 and MyD88 for adjuvant monophosphoryl lipid A (MPLA) activity in a DNA prime-protein boost HIV-1 vaccine. Vaccine 32:5049-56|
|Chen, Yuxin; Vaine, Michael; Wallace, Aaron et al. (2013) A novel rabbit monoclonal antibody platform to dissect the diverse repertoire of antibody epitopes for HIV-1 Env immunogen design. J Virol 87:10232-43|
|Buglione-Corbett, Rachel; Pouliot, Kimberly; Marty-Roix, Robyn et al. (2013) Serum cytokine profiles associated with specific adjuvants used in a DNA prime-protein boost vaccination strategy. PLoS One 8:e74820|
|Pan, Ruimin; Sampson, Jared M; Chen, Yuxin et al. (2013) Rabbit anti-HIV-1 monoclonal antibodies raised by immunization can mimic the antigen-binding modes of antibodies derived from HIV-1-infected humans. J Virol 87:10221-31|
|Murphy, Megan K; Yue, Ling; Pan, Ruimin et al. (2013) Viral escape from neutralizing antibodies in early subtype A HIV-1 infection drives an increase in autologous neutralization breadth. PLoS Pathog 9:e1003173|
|O'Connell, Olivia; Repik, Alexander; Reeves, Jacqueline D et al. (2013) Efficiency of bridging-sheet recruitment explains HIV-1 R5 envelope glycoprotein sensitivity to soluble CD4 and macrophage tropism. J Virol 87:187-98|
|Peters, Paul J; Richards, Kathryn; Clapham, Paul (2013) Human immunodeficiency viruses: propagation, quantification, and storage. Curr Protoc Microbiol Chapter 15:Unit 15J.1|
|Gonzalez-Perez, Maria Paz; O'Connell, Olivia; Lin, Rongheng et al. (2012) Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue. Retrovirology 9:20|
|Duenas-Decamp, Maria J; O'Connell, Olivia J; Corti, Davide et al. (2012) The W100 pocket on HIV-1 gp120 penetrated by b12 is not a target for other CD4bs monoclonal antibodies. Retrovirology 9:9|
Showing the most recent 10 out of 22 publications