Developing humanized mouse models for the study of HIV-1 latency and viral eradication

 描述(由申请人提供)：尽管进行了极其有效的联合抗逆转录病毒治疗(CART)，但HIV-1仍然存在于一小群潜伏感染的、静止的记忆CD4+T细胞中。在治疗中断后，病毒会迅速反弹。因此，需要终生抗逆转录病毒治疗，这引发了人们对数十年治疗的不良反应、耐药性的演变以及慢性治疗的经济负担的担忧。目前清除潜伏库的方法包括通过逆转病毒潜伏期的药物重新激活HIV-1转录。下一步是消灭感染艾滋病毒-1基因的细胞 转录是由潜伏期反转剂(LRA)诱导的。到目前为止，还没有制定出广泛适用的策略来有效清除体内潜伏的HIV-1。两个主要障碍阻碍了我们制定有效的策略来消除潜伏的HIV-1：1)缺乏对患者体内潜伏的病毒库的细胞组成和解剖位置的了解；2)缺乏体内实验系统来评估LRA的疗效和清除潜伏的HIV-1的疫苗策略。我在最近开发的人源化小鼠模型MISTRG中研究了HIV-1感染，MISTRG支持人类淋巴系和髓系细胞的共同发育。我已经证明，这种新的小鼠模型可以使我们能够研究HIV-1在CD4+T细胞和多个单核细胞和巨噬细胞亚群中的感染。在拟议的工作中，我将利用进一步改进的MISTRG小鼠模型来系统地研究体内HIV-1潜伏感染，并开发清除潜伏病毒库的治疗策略。在K99阶段，首先建立有效CART下HIV-1潜伏期的人源化小鼠模型。利用这个动物模型，我将研究HIV-1潜伏感染巨噬细胞以及次级淋巴器官和包括肠道在内的周围组织中的CD4+T细胞。在建立了HIV-1潜伏感染的MISTRG模型后，我将研究潜伏库中的HIV-1 CTL逃逸变异及其对LRA治疗的反应，并设计新的疫苗接种策略，以增强粘膜组织中HIV-1特异性CTL反应，以清除病毒(R00期)。总体而言，这些研究将为治愈艾滋病毒/艾滋病提供科学基础和临床前证据。

 DESCRIPTION (provided by applicant): Despite extremely effective combination antiretroviral therapy (cART), HIV-1 persists in a small pool of latently infected, resting memory CD4+ T cells. Rapid viral rebound occurs after treatment interruptions. Therefore, life-long antiretroviral therapy is required, raising concerns about adverse effects over decades of therapy, the evolution of drug resistance, and the financial burden of chronic treatment. Current approaches to purging the latent reservoir involve pharmacologic reactivation of HIV-1 transcription by agents that reverse viral latency. The next step is to eliminate infected cells in which HIV-1 gene transcription has been induced by latency reversal agents (LRAs). To date, no broadly applicable strategy has been developed to effectively clear latent HIV-1 in vivo. Two major obstacles have prevented us from developing effective strategies to eliminate latent HIV-1 are: 1) the lack of understanding of cellular composition and anatomical location of the latent viral reservoirs in patients; and 2) the paucity of in vivo experimental systems with which to assess LRA efficacy and vaccination strategies to clear latent HIV-1. I studied HIV-1 infection in recently developed humanized mouse model named MISTRG, which supports co-development of human lymphoid and myeloid lineage cells. I have demonstrated that this novel mouse model could enable us to study HIV-1 infection in CD4+ T cells and multiple subsets of monocytes and macrophages. In the proposed work, I will utilize further improved MISTRG mouse models to systemically investigate HIV-1 latent infection in vivo and develop therapeutic strategies to purge latent viral reservoir. In K99 phase, I will first establish a humanized mouse model of HIV-1 latency under effective cART. With this animal model, I will investigate HIV-1 latent infection i macrophages as well as CD4+ T cells in secondary lymphoid organs and peripheral tissues including gut. Having developed MISTRG model for HIV-1 latent infection, I will study HIV-1 CTL escape variants in the latent reservoir, their response to LRA treatment, and design novel vaccination strategies to boost HIV-1-specific CTL responses at mucosal tissues for viral clearance (R00 phase). Overall, these studies will provide a scientific basis and preclinical evidence of a cure for HIV/AIDS.