Virus production from HIV reservoirs

描述(申请人提供)：病毒库无限期地持续存在，具有助长病毒反弹的能力，是消除艾滋病毒感染的主要障碍。确定艾滋病毒-1病毒的储存库和抗逆转录病毒疗法(ARV)不能完全抑制艾滋病毒-1病毒复制的庇护所，将有助于探索改善治疗结果的新方法，对于今后从体内消除艾滋病毒-1病毒的努力至关重要。尽管进行了广泛的研究，但在接受抗逆转录病毒治疗的宿主中保留艾滋病毒宿主和避难所的位置和机制仍然知之甚少。从历史上看，了解病毒库的努力主要集中在容易接触到的组织部位，如体循环、浅层淋巴结和生殖器液体。最近，一些小型研究试图检查其他部位，如大肠和小肠的肠道相关淋巴组织(GALT)、细支气管肺泡灌洗、脑脊液和肾脏。然而，我们和其他人已经证明，一旦停止治疗或失败，外周血和淋巴结内的潜伏感染细胞并不是反弹病毒的重要来源，这些反弹病毒群体的来源尚不清楚。因此，迫切需要对受感染宿主内的病毒库进行全面调查。为此，我们开发了创新的计算工具，用于从病毒基因序列数据中识别病毒库和病毒室。鉴定储存库和评估储存库保留机制的理想材料来源是对高尔特(Galt；65%的T淋巴细胞被定位，在HIV-1感染早期是病毒复制的主要部位)和来自在抑制ART中死亡的个人的尸检组织的侵入性检查。目前，由于很难找到符合这些标准的受试者，这些研究领域实际上仍未被探索。然而，我们已经从符合我们标准的几个人身上鉴定并获得了组织，并获得了更多对照组中死于艾滋病但未接受抗逆转录病毒治疗的个人的尸检。在这里，我们建议在抗逆转录病毒治疗期间系统地探索全身潜伏的病毒储存库和活跃病毒复制的避难所。我们建议从抑制ART期间的GALT和在抑制ART期间死亡的个人的尸检组织中提取HIV-1RNA和DNA序列，评估病毒储存库的特征，并识别具有正在进行的病毒复制避难所特征的组织。 与公共卫生相关：病毒库无限期地持续存在，具有推动病毒反弹的能力，是消除艾滋病毒感染的主要障碍。确定艾滋病毒-1病毒的储存库和抗逆转录病毒疗法(ARV)不能完全抑制艾滋病毒-1病毒复制的庇护所，将有助于探索改善治疗结果的新方法，对于今后从体内消除艾滋病毒-1病毒的努力至关重要。在这里，我们建议在抗逆转录病毒治疗期间系统地探索全身潜伏的病毒储存库和活跃病毒复制的避难所。

DESCRIPTION (provided by applicant): The indefinite persistence of virus reservoirs, with the capacity to fuel virus rebound, is the major obstacle to eliminating HIV infection. Identifying reservoirs of HIV-1 and sanctuaries where HIV-1 replication is not completely suppressed by antiretroviral (ARV) therapy (ART) will facilitate the exploration of new approaches to improve treatment outcomes, and will be critical to future efforts to eliminate HIV-1 from the body. Despite extensive study, the location and mechanisms for retention of HIV reservoirs and sanctuaries in the ARV treated host remain poorly understood. Historically, efforts to understand virus reservoirs have centered on easily accessible tissue sites such as the systemic circulation, superficial lymph nodes, and genital fluids. More recently, a few small studies have attempted to examine other sites such as Gut-associated lymphoid tissues (GALT) in the large and small bowel, bronchioalveolar lavage, CSF and kidney. However, we and others have demonstrated that latently infected cells within the peripheral blood and lymph nodes are not significant sources of rebounding virus once therapy is withdrawn or fails, and the origins of these rebounding virus populations remain unclear. A comprehensive investigation of virus reservoirs within the infected host is therefore urgently needed. To this end, we have developed innovative computational tools for the identification of virus reservoirs and compartments from viral gene sequence data. The ideal source of materials for identifying reservoirs, and for assessing mechanisms of retention of reservoirs, would be an invasive examination of both GALT (where >65% of all T-lymphocytes are localized, and the major site of virus replication early in HIV-1 infection) and autopsy-derived tissues from individuals who died while on suppressive ART. Presently, these research areas remain virtually unexplored due to the difficulty in finding subjects that fit these criteria. However, we have identified and obtained tissues from several individuals meeting our criteria and have access to many more autopsies of individuals forming the control group that have died of AIDS while not on ART. Here we propose to systematically explore the entire body for latent viral reservoirs and sanctuaries of active viral replication during ART. We propose to derive HIV-1 RNA and DNA sequences from GALT during suppressive ART, and autopsy tissues from individuals who died while on or not on suppressive ART, appraise the sequences for features of viral reservoirs, and identify tissues with features of sanctuaries of ongoing viral replication. PUBLIC HEALTH RELEVANCE: The indefinite persistence of virus reservoirs, with the capacity to fuel virus rebound, is the major obstacle to eliminating HIV infection. Identifying reservoirs of HIV-1 and sanctuaries where HIV-1 replication is not completely suppressed by antiretroviral (ARV) therapy (ART) will facilitate the exploration of new approaches to improve treatment outcomes, and will be critical to future efforts to eliminate HIV-1 from the body. Here we propose to systematically explore the entire body for latent viral reservoirs and sanctuaries of active viral replication during ART.