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 虽然目前的抗逆转录病毒（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。ART治疗的个体仍然会出现几种合并症，包括 增加心血管疾病、骨骼疾病和认知障碍。最重要的是，治疗 中断导致病毒复制和艾滋病进展的重新出现。因此发展 迫切需要一系列旨在根除或功能性治愈艾滋病毒感染的新方法。休克- “即杀即治”战略是根除艾滋病毒的有希望的办法。然而，潜伏感染的细胞， 潜伏期逆转剂诱导的病毒产生不太可能在缺乏 有效的免疫反应。一种替代的，也许更现实的方法，以消除潜伏感染 病毒再活化后的细胞依赖于免疫细胞介导抗体依赖性细胞免疫的能力。 细胞毒性（ADCC）。通过ADCC，效应细胞如NK细胞和单核细胞可以杀死感染的细胞 通过HIV特异性抗体的识别表达包膜糖蛋白（Env）。因为艾滋病毒- 1 Vpu和Nef蛋白使ADCC的主要靶点Env-CD 4复合物远离细胞表面，这种免疫 机制自然相对低效。然而，我们最近发现，CD 4模拟化合物 （CD 4 mc）能够推动HIV-1包膜糖蛋白（Env）对CD 4结合构象进行采样， 导致HIV-1感染的细胞对ADCC敏感。我们的观察表明，CD 4 mc可能是 这对“休克和杀死”战略中的“杀死”部分有用，以清除艾滋病毒储存库，因此可以 具有在再活化时减小病毒储库的大小的治疗效用。的目的 该建议是为CD 4 mc在减少病毒储存库的大小方面的价值提供概念证明， SHIV感染的恒河猴，这可以加快应用于HIV-1感染的人类。