Characterizing HIV-1 Env conformations susceptible to attack by non-neutralizing antibodies

表征易受非中和抗体攻击的 HIV-1 Env 构象

• 批准号: 9925626
• 负责人: Andres Finzi
• 金额: $ 58.8万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-23 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9925626
• 关键词: Acquired Immunodeficiency Syndrome; Adopted; Adoption; Affect; Antibodies; Antibody Activation; Antigens; Binding; Binding Sites; Biological Assay; Bone Diseases; Cardiovascular Diseases; Cells; Characteristics; Cryoelectron Microscopy; Data; Development; Elements; Enzyme-Linked Immunosorbent Assay; Epidemic; Epitopes; Event; Fluorescence Resonance Energy Transfer; Future; Generations; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; HIV-1 vaccine; Health; Image; Immune; Immunoglobulin A; Impaired cognition; In Vitro; Individual; Infection; Interruption; Investigation; Lead; Mediating; Molecular; Molecular Conformation; Plasma; Predisposition; Research; Research Personnel; Structure; Techniques; Testing; Thailand; Viral; Viral reservoir; Virus; Virus Replication; X-Ray Crystallography; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; comorbidity; design; experience; fluorescence imaging; immunological status; improved; insight; interdisciplinary approach; latent HIV reservoir; novel; novel strategies; novel therapeutics; prevent; prophylactic; protective efficacy; response; single molecule; success; vaccine trial

SUMMARY While current antiretroviral therapies (ART) are able to control HIV replication, they are unable to fully restore health or a normal immune status. ART-treated individuals still experience several co-morbidities including increased cardiovascular disease, bone disorders, and cognitive impairment. Most importantly, therapy interruption leads to the re-emergence of viral replication and progression to AIDS. Therefore, new approaches aimed at eradicating or functionally curing HIV infection are desperately needed. An under-studied strategy to eliminate latently infected cells after viral reactivation relies on the ability of immune cells to mediate antibody- dependent cellular cytotoxicity (ADCC). The RV144 HIV-1 vaccine trial in Thailand elicited a 31.2% protective efficacy, making it the first vaccine trial with any level of success in generating a protective response. Subsequent analyses indicated that this modest protection was correlated with the generation of antibodies (Abs) with high ADCC activity, in the presence of low plasma IgA Env-specific Abs. This suggests that ADCC may have contributed to the protection observed in the RV144 trial. But key unanswered questions exist that prevent researchers from specifically triggering the ADCC response with novel treatments or immunogens: Why did the RV144 trial generate such a strong ADCC response? What about the CRF01_AE subtype of HIV-1, which predominates the Thai AIDS epidemic, might make it especially susceptible to ADCC? Does Env conformation affect ADCC responses? Answering these questions will prove crucial to the design of improved strategies to eliminate HIV-1-infected cells. The long-term goal of the research described in this proposal is to inform the development of new strategies for utilizing the ADCC response to eradicate the HIV-1 infection. To achieve this goal, we will begin by describing in molecular detail the Env conformations that are susceptible to attack by Abs that induce ADCC, and to determine the structural elements of Env from distinct HIV-1 strains that mediate transition to these conformations. Our central hypothesis is that Env has intrinsic access to downstream conformations that are recognized by easily-elicited non-neutralizing Abs. Some of which, like the anti-cluster A Abs, have potent ADCC activity. In support of this hypothesis, we recently demonstrated using Ab-binding assays, cryo-electron microscopy (Cryo-EM), and single-molecule Förster resonance energy transfer (smFRET) imaging that HIV-1 Env can adopt a conformation that is sensitive to attack by Abs that have potent ADCC activity (State 2A). The rationale underlying this proposal is that characterization of the structure of Env State 2A, as wells as other conformations recognized by non-neutralizing Abs, and the elements that mediate stabilization of these conformations will inform new strategies to eliminate the latent HIV reservoir.

概括 虽然目前的抗逆转录病毒疗法（ART）能够控制HIV复制，但他们无法完全恢复 健康或正常的免疫状况。经过艺术治疗的人仍然经历了几种合并症 心血管疾病，骨骼疾病和认知障碍增加。最重要的是治疗 中断导致病毒复制和进展为艾滋病的重新出现。因此，新方法 迫切需要旨在根除或在功能上治愈艾滋病毒感染。研究不足的策略 病毒重新激活后消除了横向感染的细胞，取决于免疫细胞介导抗体的能力 依赖性细胞毒性（ADCC）。泰国的RV144 HIV-1疫苗试验引起了31.2％的保护 功效，使其成为第一个在产生受保护反应的任何成功水平的疫苗试验中。随后的 分析表明，这种适度的保护与高产生的抗体（ABS）相关 在低血浆IGA ENV特异性ABS的情况下，ADCC活性。这表明ADCC可能有 有助于在RV144试验中观察到的保护。但是存在预防的关键未解决问题 研究人员专门触发ADCC反应，使用新型治疗或免疫原子：为什么 RV144试验产生了如此强大的ADCC响应？ HIV-1的CRF01_AE亚型呢？ 泰国艾滋病的流行可能会使ADCC特别容易受到影响？ env构象 影响ADCC的回应？回答这些问题将证明对改进策略的设计至关重要 消除HIV-1感染的细胞。本提案中描述的研究的长期目标是通知 制定利用ADCC反应来消除HIV-1感染的新策略。实现这一目标 目标，我们将从分子细节中描述容易受到ABS攻击的ENV构象开始 这会影响ADCC，并从介导的不同HIV-1菌株中确定ENV的结构元素 过渡到这些构象。我们的中心假设是ENV具有内在的下游访问 通过易于引起的非中和腹肌识别的构象。其中一些，例如反群集a ABS，具有潜在的ADCC活性。为了支持这一假设，我们最近使用AB结合证明了 测定，冷冻电子显微镜（Cryo-EM）和单分子Förster共振能量转移（SMFRET） 成像HIV-1 Env可以采用对具有潜在ADCC的ABS攻击敏感的会议 活动（状态2a）。该提议的基本原理是，env状态结构的特征 2a，以及通过非中和ABS认可的其他构型，以及介导的元素 这些构象的稳定将为消除潜在的艾滋病毒水库的新策略提供信息。