Env-Ab coevolution in SHIV infected RMs leading to V3 glycan bNAbs

SHIV 感染 RM 中的 Env-Ab 共同进化导致 V3 聚糖 bNAb

• 批准号: 10370983
• 负责人: GEORGE M SHAW
• 金额: $ 140.56万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-07 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370983
• 关键词: Affinity; Animals; Antibodies; Antibody Affinity; Antibody Response; Antigens; Autologous; B-Lymphocytes; Binding Sites; Biological; Data; Data Set; Development; Epitopes; Foundations; Frequencies; Glycopeptides; Goals; HIV-1; HIV-1 vaccine; Human; Immunization; Immunize; Immunologics; Infection; Lead; Length; Link; Macaca mulatta; Mannose; Modeling; Molecular; Molecular Analysis; Monoclonal Antibodies; Mutation; Pathway interactions; Peptides; Polysaccharides; Prevalence; Primates; Process; Program Research Project Grants; Reproducibility; Reverse engineering; Rhesus; Scheme; Scientific Advances and Accomplishments; Specificity; Speed; Structure; Testing; Ursidae Family; Vaccination; Vaccine Design; Vaccine Research; Virus; Virus Diseases; Work; arm; base; design; immunogenicity; innovation; nanoparticle delivery; neutralizing antibody; nonhuman primate; novel; response; simian human immunodeficiency virus; vaccine trial

PROJECT SUMMARY A major roadblock to rational HIV-1 vaccine design is the lack of a suitable primate model in which broadly neutralizing antibodies (bNAbs) can be consistently induced and the underlying molecular, biological and immunological mechanisms studied in an iterative fashion. Since most HIV-1 bNAbs have come from humans infected by HIV-1, we hypothesized that one means to elicit bNabs in primates might be by infecting rhesus macaques (RMs) with simian-human immunodeficiency virus (SHIV) strains that bear primary or transmitted/founder HIV-1 Envs, including those that induced bNAbs in humans. SHIV infected RMs could then be employed to assess the potential of different HIV-1 Envs to elicit bNAbs and to characterize the coevolutionary pathways of bNAb lineages and cognate Envs that elicited them, thereby serving as a “molecular guide” for rational vaccine design. Recent innovations in SHIV design by our lab have made this experimental strategy testable. In this renewal application, we show that 24 of 150, or 16%, of RMs infected by SHIVs bearing different primary HIV-1 Envs developed bNAbs targeting V3 glycan, V2 apex, CD4bs or fusion peptide epitopes. Nine of these animals developed V3 glycan bNAbs. From this extensive dataset, we identified HIV-1 CH848 and BG505.N332 Envs as immunogens that most consistently elicited V3 glycan bNAbs in RMs. We further showed that by reducing the length of V1 and the number of potential N-linked glycans in V1 (designated CH848.dV1 and BG505.N332.dV1), we could enhance the frequency and speed of induction of V3 glycan bNAbs in SHIV infected RMs. Based on these findings, we propose in this project to test the hypothesis that infection of RMs by SHIV.CH848.dV1 or SHIV.BG505.N332.dV1 will selectively prime V3 glycan bNAb lineage B cell precursors, and through a process of Env-Ab coevolution, mature these responses to achieve neutralization breadth. Moreover, by identifying evolved Env intermediates that select for V3 glycan bNAb affinity maturation, we can design lineage-based Env immunogens that, when constructed as SOSIP Env trimers and used to immunize outbred RMs, will elicit V3 glycan bNAbs that are protective against heterologous virus challenge. Specific Aims are: (i) to decipher molecular pathways of Env-Ab coevolution in SHIV-infected RMs that lead to the development of V3 glycan bNAbs, including the identification of inferred germline bNAb precursors, bNAb lineage intermediates and evolved Env intermediates that select for affinity maturation and neutralization breadth; (ii) to evaluate the ability of nanoparticle-delivered, germline-targeted CH848.dV1 and BG505.N332.dV1 SOSIP Env trimers to prime V3 glycan bNAb lineage precursors and for subsequent homologous SHIV infection to select for affinity maturation and neutralization breadth; and (iii) to conduct a statistically-powered, proof-of-concept vaccine trial in RMs testing the hypothesis that germline-targeted, B lineage-designed SOSIP Env trimers can prime, boost and affinity mature V3 glycan bNAb responses to an extent that is superior to conventional SOSIP Env immunogens and that protects RMs from heterologous virus challenge.

项目总结