Virus production from HIV reservoirs

HIV 病毒库的病毒生产

基本信息

批准号：
7818420
负责人：
JAMES Ivan MULLINS
金额：
$ 49.95万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-26 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7818420
关键词：
Acquired Immunodeficiency Syndrome Anti-Retroviral Agents Appearance Area Attention Autopsy Blood Blood Circulation Bronchoalveolar Lavage CD4 Positive T Lymphocytes Cells Chronic Clinical Clinical Treatment Commit Control Groups Cytotoxic T-Lymphocytes DNA Sequence Data Detection Disease Progression Disease Resistance Drug resistance Drug toxicity Evolution Failure Forms Controls Functional disorder Future Genital system Gut associated lymphoid tissue HIV HIV Infections HIV-1 Individual Infection Investigation Kidney Life Light Liquid substance Location Lymphocyte Measures Methods Outcome Pathogenesis Patients Persons Pharmaceutical Preparations Phenotype Population Production RNA Research Role Sampling Shapes Site Small Intestines Source T-Lymphocyte Tissues Treatment Failure Treatment outcome Tropism Variant Viral Viral Genes Virus Virus Replication analytical method antiretroviral therapy cohort computerized tools coping drug resistant virus experience improved innovation lymph nodes meetings novel strategies peripheral blood public health relevance resistant strain response stem tissue tropism virus host interaction virus identification

项目摘要

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.

描述（由申请人提供）：病毒储存库的无限期存留以及加速病毒反弹的能力是消除艾滋病毒感染的主要障碍。确定 HIV-1 的储存库和抗逆转录病毒 (ARV) 疗法 (ART) 未完全抑制 HIV-1 复制的庇护所将有助于探索改善治疗结果的新方法，并且对于未来消除 HIV-1 的努力至关重要来自身体。尽管进行了广泛的研究，但对抗逆转录病毒治疗宿主体内艾滋病病毒储存库和庇护所的保留位置和机制仍然知之甚少。从历史上看，了解病毒储存库的努力主要集中在易于接近的组织部位，例如体循环、浅表淋巴结和生殖器液体。最近，一些小型研究尝试检查其他部位，例如大肠和小肠中的肠道相关淋巴组织 (GALT)、支气管肺泡灌洗液、脑脊液和肾脏。然而，我们和其他人已经证明，一旦治疗撤回或失败，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，并且这些反弹病毒群体的起源仍不清楚。因此，迫切需要对受感染宿主体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区室。识别储存库和评估储存库保留机制的理想材料来源是对 GALT（所有 T 淋巴细胞的 65% 以上是局部的）和 HIV 早期病毒复制的主要位点进行侵入性检查。 1 感染）和来自接受抑制性 ART 期间死亡的个体的尸检组织。目前，由于很难找到符合这些标准的主题，这些研究领域实际上仍未被探索。然而，我们已经从几位符合我们标准的个体中鉴定并获得了组织，并获得了对照组中未接受抗逆转录病毒治疗时死于艾滋病的更多个体的尸检。在这里，我们建议在 ART 期间系统地探索整个身体的潜在病毒库和活跃病毒复制的避难所。我们建议从抑制性 ART 期间的 GALT 中获取 HIV-1 RNA 和 DNA 序列，以及在接受或未接受抑制性 ART 期间死亡的个体的尸检组织，评估病毒储存库特征的序列，并识别具有正在进行的庇护所特征的组织。病毒复制。公共卫生相关性：病毒库的无限期存留以及加速病毒反弹的能力是消除艾滋病毒感染的主要障碍。确定 HIV-1 的储存库和抗逆转录病毒 (ARV) 疗法 (ART) 未完全抑制 HIV-1 复制的庇护所将有助于探索改善治疗结果的新方法，并且对于未来消除 HIV-1 的努力至关重要来自身体。在这里，我们建议在 ART 期间系统地探索整个身体的潜在病毒库和活跃病毒复制的避难所。