Integrated HIV DNA in CNS and Deep Body Compartments

中枢神经系统和深部身体区室中整合的 HIV DNA

• 批准号: 9008075
• 负责人: BENJAMIN B. GELMAN
• 金额: $ 27.13万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-02 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008075
• 关键词: Acceleration; Address; Antigens; Astrocytes; Blood; Brain; Cells; Cessation of life; Characteristics; DNA; Data; Genes; Genetic Transcription; Genome; Gray unit of radiation dose; HIV; HIV Infections; Health; Highly Active Antiretroviral Therapy; Histocompatibility Testing; Human; Human Genome; Human body; Infection; Latent Virus; Lead; Lymphocyte; Lymphoid Tissue; Maps; Measures; Medicine; Memory; Microglia; Mononuclear; Neuraxis; Neurocognitive Deficit; Organ; Penetration; Phagocytes; Phenotype; Plasma; Population; Rest; Sampling; Specimen; T-Lymphocyte; Testing; Time; Tissues; Virus Latency; Virus Replication; Work; base; cell type; histiocyte; human tissue; macrophage; programs; white matter

DESCRIPTION (provided by applicant): In HIV-infected subjects taking HAART, in whom HIV replication has been substantially suppressed, HIV infection is not eradicated. Viral latency occurs when HIV DNA becomes integrated into the genome of human cells during the cycle of infection, and then becomes transcriptionally silent (or nearly so). There is a small cache of resting T lymphocytes in the body that contains non-transcribed HIV DNA (or very slowly transcribed) that is integrated into the human genome. Without transcription of HIV genes these infected T cells presumably do not present foreign antigen. They are immunologically "inert," their HIV DNA becomes transcriptionally "silenced," and the infection is latent. The turning over of T cells that contain latent HIV infection is not rapid enough to achieve their elimination naturally over time while taking HAART. Based primarily upon data gathered from sampling lymphocytes in blood plasma, it is widely suggested that the eradication of HIV infection could be achieved if new measures are taken to eliminate cells that contain latent HIV, especially the small proportion of T cells that harbor HIV latency. To find cellular caches of latent HIV in the body and eliminate them challenges must be faced: 1) Do changes in lymphocytes sampled from blood plasma samples obtained clinically reflect what occurs in deep body compartments, especially non-lymphoid organs including the central nervous system (CNS), in which infection is primarily in macrophages, microglia and astrocytes? 2) Is there a macrophage/microglial phenotype in the CNS and/or tissue histiocytes of deep organ compartments that specifically support HIVlat that should be selectively targeted for elimination? 3) Are the cellular caches of HIVint in the CNS and other deep body compartments distributed homogeneously, and in characteristic cell types? Of special concern is that latency in mononuclear phagocytes, which includes the widespread tissue histiocytes of the body, is not understood. These are the cells that are critical reservoirs in the central nervous system (CNS) and other non-lymphoid types of tissue. These basic questions are difficult to address clinically because access to human tissue specimens is necessary. This program of study will utilize tissue specimens from well characterized subject who were infected with HIV to define the cellular caches of HIV DNA that has been integrated into the human genome, and thus, could contribute to HIV in the body latency. One aim will define this pool of HIV DNA in the CNS. A second aim will produce similar data in other deep tissue compartments of the human body. These data will assist the field in targeting cells that harbor latent virus so that they can be eradicated.

描述（由申请人提供）：在接受HAART的HIV感染受试者中，HIV复制已被显着抑制，但HIV感染并未被根除。当 HIV DNA 在感染周期中整合到人类细胞的基因组中，然后变得转录沉默（或接近沉默）时，就会出现病毒潜伏期。体内有一小部分静息 T 淋巴细胞，其中含有未转录的 HIV DNA（或转录非常缓慢），已整合到人类基因组中。如果没有 HIV 基因的转录，这些受感染的 T 细胞可能不会呈递外源抗原。它们在免疫学上是“惰性的”，它们的HIV DNA在转录上变得“沉默”，并且感染是潜伏的。在接受 HAART 治疗期间，含有潜伏 HIV 感染的 T 细胞的更新速度不够快，无法随着时间的推移自然消除。主要基于从血浆中淋巴细胞采样中收集的数据，人们普遍认为，如果采取新措施消除含有潜伏HIV的细胞，特别是一小部分含有HIV潜伏的T细胞，则可以实现根除HIV感染。为了找到体内潜伏 HIV 的细胞缓存并消除它们，必须面对以下挑战：1) 从临床获得的血浆样本中采集的淋巴细胞的变化是否反映了身体深层部位发生的情况，特别是包括中枢神经系统在内的非淋巴器官（ CNS），其中感染主要发生在巨噬细胞、小胶质细胞和星形胶质细胞中？ 2) 中枢神经系统和/或深层器官区室的组织细胞中是否存在专门支持 HIVlat 的巨噬细胞/小胶质细胞表型，应选择性地靶向消除？ 3) 中枢神经系统和其他深部身体区室中的 HIVint 细胞缓存是否均匀分布且以特征细胞类型分布？特别值得关注的是，单核吞噬细胞（包括体内广泛的组织细胞）的潜伏期尚不清楚。这些细胞是中枢神经系统 (CNS) 和其他非淋巴组织类型的关键储存细胞。这些基本问题在临床上很难解决，因为需要获取人体组织标本。该研究计划将利用来自感染 HIV 的明确特征受试者的组织样本来确定已整合到人类基因组中的 HIV DNA 的细胞缓存，从而可能导致 HIV 在体内潜伏。一个目标是定义中枢神经系统中的艾滋病毒 DNA 库。第二个目标是在人体的其他深层组织区室中产生类似的数据。这些数据将有助于该领域瞄准含有潜伏病毒的细胞，以便将其根除。