Reducing viral reservoirs by opening HIV-1 Env to antibody attack

通过打开 HIV-1 包膜以应对抗体攻击来减少病毒储存

• 批准号: 9258013
• 负责人: JOSEPH G SODROSKI
• 金额: $ 21.62万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9258013
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Anti-Retroviral Agents; Antibodies; Antigens; Autologous; Biological; Biological Markers; Blood specimen; Bone Diseases; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cardiovascular Diseases; Cell surface; Cells; Chemistry; Comorbidity; Complete Blood Count; Complex; Control Groups; Development; Dose; Down-Regulation; Drug Kinetics; Effector Cell; Glycoproteins; HIV; HIV Infections; HIV-1; Health; Human; Immune; Immune response; Impaired cognition; Individual; Infection; Interruption; Macaca mulatta; Measurement; Measures; Mediating; Modeling; Molecular Conformation; Natural Killer Cells; Phase; Plasma; Production; Property; RNA; Regimen; Safety; Sampling; Serum; Shock; Structure; Surface; Testing; Therapeutic; Tissue Sample; Tissues; Toxic effect; Variant; Viral; Viral Load result; Viral reservoir; Virus; Virus Replication; activity marker; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; cell killing; cellular sensitization; cytokine; experience; experimental study; immunological status; in vivo; inflammatory marker; killings; mimetics; monocyte; nef Protein; nonhuman primate; novel strategies; particle; prevent; purge; simian human immunodeficiency virus; viral rebound; vpu Protein

Project Summary While current antiretroviral (ART) therapies are able to control viral 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 AIDS progression. Therefore, the development of new approaches aimed at eradicating or functionally curing HIV infection are desperately needed. Shock- and-kill strategies represent promising approaches to HIV eradication. However, latently infected cells in which viral production has been induced by latency-reversing agents are unlikely to be depleted in the absence of an efficient immune response. An alternative and perhaps more realistic approach to eliminate latently infected cells after viral reactivation relies on the ability of immune cells to mediate antibody-dependent cellular cytotoxicity (ADCC). Through ADCC, effector cells such as NK cells and monocytes can kill infected cells expressing the envelope glycoproteins (Env) through recognition by HIV-specific antibodies. Because the HIV- 1 Vpu and Nef proteins keep Env-CD4 complexes, the major target for ADCC, off the cell surface, this immune mechanism is naturally relatively inefficient. However, we recently discovered that CD4-mimetic compounds (CD4mc) are able to push the HIV-1 envelope glycoproteins (Env) to sample the CD4-bound conformation, resulting in sensitization of HIV-1-infected cells to ADCC. Our observations suggest that CD4mc could be useful for the "kill" part of the "shock-and-kill" strategy being pursued to purge the HIV reservoir, and thus could have therapeutic utility in decreasing the size of the viral reservoir upon reactivation. The objective of this proposal is to provide a proof of concept for the value of CD4mc in reducing the size of the viral reservoir in SHIV-infected rhesus macaques, which could expedite application to HIV-1-infected humans.

项目摘要 虽然当前的抗逆转录病毒（ART）疗法能够控制病毒复制，但它们无法完全恢复 健康或正常的免疫状态。经过艺术治疗的人仍然经历了几种合并症 增加心血管疾病，骨骼疾病和认知障碍。最重要的是治疗 中断导致病毒复制的重新出现并有助于进展。因此，发展 迫切需要旨在消除或在功能上治愈艾滋病毒感染的新方法。震惊- 和杀伤策略代表了消除艾滋病毒的有前途的方法。但是，潜在感染的细胞，其中 在不存在的情况下，不太可能耗尽病毒的产生。 有效的免疫反应。一种消除潜在感染的替代方法，也许更现实的方法 病毒重新激活后的细胞取决于免疫细胞介导抗体依赖性细胞的能力 细胞毒性（ADCC）。通过ADCC，效应细胞（例如NK细胞和单核细胞）可以杀死受感染的细胞 通过HIV特异性抗体识别来表达包膜糖蛋白（ENV）。因为艾滋病毒 - 1 VPU和NEF蛋白保持Env-CD4复合物，这是ADCC的主要靶标，远离细胞表面，这种免疫 机制自然相对效率低下。但是，我们最近发现CD4模拟化合物 （CD4MC）能够推动HIV-1包膜糖蛋白（ENV）采样CD4结合构象， 导致HIV-1感染细胞对ADCC的敏化。我们的观察结果表明CD4MC可能是 对于清除艾滋病毒水库的“震惊和杀伤”策略的“杀死”一部分有用，因此 重新激活后具有治疗效用，以减少病毒储存剂的大小。这个目的 建议是为CD4MC的价值提供概念证明 Shiv感染的恒河猕猴，可以加快对HIV-1感染的人类的应用。