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

开发用于研究 HIV-1 潜伏期和病毒根除的人源化小鼠模型

• 批准号: 9141745
• 负责人: LIANG SHAN
• 金额: $ 13.31万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9141745
• 关键词: AIDS/HIV problem; Address; Adverse effects; Aftercare; Animal Model; CD4 Positive T Lymphocytes; Cell Lineage; Cells; Chronic; Development; Drug resistance; Epitopes; Evolution; Genetic Transcription; HIV-1; Human; Infection; Interruption; Latent Virus; Life; Location; Longitudinal Studies; Lymphoid; Modeling; Mucous Membrane; Mutation; Myelogenous; Names; Organ; Outcome; Patients; Peripheral; Phase; Process; Rest; System; Testing; Therapeutic; Tissues; Vaccines; Variant; Viral; Viral reservoir; Virus; Virus Latency; Work; antiretroviral therapy; base; design; humanized mouse; improved; in vivo; latent infection; macrophage; memory CD4 T lymphocyte; monocyte; mouse model; mutant; novel; peripheral blood; pre-clinical; prevent; public health relevance; purge; reproductive tract; response; therapeutic vaccine; therapy design; vaccination strategy

 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.

 描述（由申请人提供）：尽管联合抗逆转录病毒治疗（cART）非常有效，但HIV-1仍存在于一小部分潜伏感染的静息记忆CD 4 + T细胞中。治疗中断后病毒迅速反弹。因此，需要终身抗逆转录病毒治疗，这引起了人们对数十年治疗的不良反应、耐药性的演变以及长期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。下一步是消除感染细胞中的HIV-1基因 转录已被潜伏期逆转剂（LRA）诱导。迄今为止，还没有开发出广泛适用的策略来有效地清除体内潜伏的HIV-1。两个主要障碍阻碍了我们开发消除潜伏HIV-1的有效策略：1）缺乏对患者体内潜伏病毒储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疗效和疫苗接种策略以清除潜伏HIV-1。我在最近开发的名为MISTRG的人源化小鼠模型中研究了HIV-1感染，该模型支持人类淋巴和骨髓谱系细胞的共同发育。我已经证明，这种新的小鼠模型可以使我们能够研究HIV-1感染的CD 4 + T细胞和单核细胞和巨噬细胞的多个子集。在本研究中，我将利用进一步改进的MISTRG小鼠模型系统地研究HIV-1的体内潜伏感染，并开发清除潜伏病毒库的治疗策略。在K99阶段，我将首先建立有效cART下HIV-1潜伏期的人源化小鼠模型。通过该动物模型，我将研究HIV-1在次级淋巴器官和外周组织（包括肠道）中的巨噬细胞以及CD 4 + T细胞中的潜伏感染。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逃逸变体，它们对LRA治疗的反应，并设计新的疫苗接种策略来增强粘膜组织中HIV-1特异性CTL反应，以清除病毒（R 00期）。总的来说，这些研究将为治愈艾滋病毒/艾滋病提供科学依据和临床前证据。