Virus production from HIV reservoirs

HIV 病毒库的病毒生产

• 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
• 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

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）：病毒库的无限期持久性，具有燃料病毒反弹的能力，是消除HIV感染的主要障碍。鉴定HIV-1和Sanctuaries的储层，而抗逆转录病毒（ARV）疗法（ART）并未完全抑制HIV-1复制，这将有助于探索改善治疗结果的新方法，并且对于将未来消除HIV-1从体内消除HIV-1的努力至关重要。尽管进行了广泛的研究，但在ARV治疗的宿主中保留HIV储藏和庇护所的位置和机制仍然很少了解。从历史上看，了解病毒储层的努力集中在易于进入的组织部位，例如全身循环，浅表淋巴结和生殖器液。最近，一些小型研究试图检查其他部位，例如与肠道相关的淋巴组织（GALT），大小和小肠，支气管肺泡灌洗，CSF和肾脏。但是，我们和其他人已经证明，一旦撤回或失败，周围血液和淋巴结中的潜在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尚不清楚。因此，迫切需要对感染宿主内病毒储存库进行全面研究。为此，我们开发了创新的计算工具，用于鉴定病毒基因序列数据的病毒库和隔室。识别储层的理想材料来源，以及评估储层的保留机制，是对这两个Galt的侵入性检查（其中所有T淋巴细胞的65％> 65％是局部的，并且是HIV-1早期的病毒复制的主要部位），在HIV-1早期）和自动化的组织中死于抑制Arts Artivess Artsiverse Arts Artsiverse Arts Artsiverse Arts Artsiverse Arts Artsiverse Art的组织。目前，由于难以找到适合这些标准的主题，这些研究领域几乎没有探索。但是，我们已经从符合我们的标准的几个人中确定并获得了组织，并可以访问更多的人，组成对照组，而这些对照组在没有艺术的同时死于艾滋病。在这里，我们建议系统地探索整个身体的潜在病毒储存库和艺术期间主动病毒复制的庇护所。我们建议在抑制性艺术期间从GALT中得出HIV-1 RNA和DNA序列，以及在抑制或不抑制艺术期间死亡的个体的尸检组织，评估病毒储层特征的序列，并鉴定具有持续病毒复制的庇护所特征的组织。 公共卫生相关性：病毒水库的无限期持久性促进病毒反弹的能力，是消除HIV感染的主要障碍。鉴定HIV-1和Sanctuaries的储层，而抗逆转录病毒（ARV）疗法（ART）并未完全抑制HIV-1复制，这将有助于探索改善治疗结果的新方法，并且对于将未来消除HIV-1从体内消除HIV-1的努力至关重要。在这里，我们建议系统地探索整个身体的潜在病毒储存库和艺术期间主动病毒复制的庇护所。