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

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。接受抗逆转录病毒治疗的患者仍然会经历几种并存疾病，包括 心血管疾病、骨骼疾病和认知障碍的增加。最重要的是，治疗 阻断会导致病毒复制和艾滋病进展的重新出现。因此，发展 迫切需要旨在根除或从功能上治愈艾滋病毒感染的新方法。令人震惊- 和杀战略是根除艾滋病毒的有希望的方法。然而，潜伏感染的细胞 病毒的产生是由潜伏期反转剂诱导的-在没有 高效的免疫反应。一种替代的、或许更现实的消除潜伏感染的方法 病毒重新激活后的细胞依赖于免疫细胞介导抗体依赖细胞的能力 细胞毒性(ADCC)。通过ADCC，NK细胞和单核细胞等效应细胞可以杀死感染的细胞 通过HIV特异性抗体识别表达包膜糖蛋白(Env)。因为艾滋病毒- 1 VPU和Nef蛋白使Env-CD4复合体(ADCC的主要靶标)远离细胞表面，这种免疫 机制自然是相对低效的。然而，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)采样结合CD4的构象， 导致HIV-1感染细胞对ADCC敏感。我们的观察表明CD4mc可能是 对正在推行的清除艾滋病毒宿主的“电击并杀死”战略中的“杀死”部分很有用，因此可以 在重新激活时，在减少病毒库的大小方面具有治疗作用。这样做的目的是 建议为CD4mc在减少病毒库大小方面的价值提供概念证明。 希夫病毒感染的恒河猴，这可能会加快应用到感染艾滋病毒-1的人。

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.