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.
|Esteves, Pedro J; Abrantes, Joana; Baldauf, Hanna-Mari et al. (2018) The wide utility of rabbits as models of human diseases. Exp Mol Med 50:66|
|Chan, Kun-Wei; Pan, Ruimin; Costa, Matthew et al. (2018) Structural Comparison of Human Anti-HIV-1 gp120 V3 Monoclonal Antibodies of the Same Gene Usage Induced by Vaccination and Chronic Infection. J Virol 92:|
|Gonzalez-Perez, Maria Paz; Peters, Paul J; O'Connell, Olivia et al. (2017) Identification of Emerging Macrophage-Tropic HIV-1 R5 Variants in Brain Tissue of AIDS Patients without Severe Neurological Complications. J Virol 91:|
|Li, Xiaoyan; Grant, Oliver C; Ito, Keigo et al. (2017) Structural Analysis of the Glycosylated Intact HIV-1 gp120-b12 Antibody Complex Using Hydroxyl Radical Protein Footprinting. Biochemistry 56:957-970|
|Farfán-Arribas, Diego J; Liu, Shuying; Wang, Shixia et al. (2017) The dynamics of immunoglobulin V-gene usage and clonotype expansion in mice after prime and boost immunizations as analyzed by NGS. Hum Vaccin Immunother 13:2987-2995|
|Costa, Matthew R; Pollara, Justin; Edwards, Regina Whitney et al. (2016) Fc Receptor-Mediated Activities of Env-Specific Human Monoclonal Antibodies Generated from Volunteers Receiving the DNA Prime-Protein Boost HIV Vaccine DP6-001. J Virol 90:10362-10378|
|Marty-Roix, Robyn; Vladimer, Gregory I; Pouliot, Kimberly et al. (2016) Identification of QS-21 as an Inflammasome-activating Molecular Component of Saponin Adjuvants. J Biol Chem 291:1123-36|
|Suschak, John J; Wang, Shixia; Fitzgerald, Katherine A et al. (2016) A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of DNA Vaccines. J Immunol 196:310-6|
|Liu, Shuying; Wang, Shixia; Lu, Shan (2016) DNA immunization as a technology platform for monoclonal antibody induction. Emerg Microbes Infect 5:e33|
|Townsley, Samantha; Li, Yun; Kozyrev, Yury et al. (2016) Conserved Role of an N-Linked Glycan on the Surface Antigen of Human Immunodeficiency Virus Type 1 Modulating Virus Sensitivity to Broadly Neutralizing Antibodies against the Receptor and Coreceptor Binding Sites. J Virol 90:829-41|
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