Integrated HIV DNA in CNS and Deep Body Compartments

描述(由申请人提供)：在服用HAART的艾滋病毒感染者中，艾滋病毒复制已被实质性抑制，艾滋病毒感染并未被根除。当HIV DNA在感染周期中整合到人类细胞的基因组中，然后在转录上变得沉默(或几乎如此)时，病毒潜伏期就会发生。体内有一小部分静止的T淋巴细胞，其中含有整合到人类基因组中的未转录的艾滋病毒DNA(或非常慢的转录)。如果没有HIV基因的转录，这些被感染的T细胞可能不会呈现外来抗原。他们在免疫上是“惰性的”，他们的艾滋病毒DNA在转录上变得“沉默”，感染是潜伏的。在服用HAART的同时，含有潜伏的HIV感染的T细胞的翻转速度不够快，无法随着时间的推移自然消除它们。主要基于从血浆中采集的淋巴细胞样本收集的数据，人们普遍认为，如果采取新的措施消除含有潜伏的HIV的细胞，特别是含有HIV潜伏的一小部分T细胞，那么根除HIV感染是可以实现的。为了找到体内潜伏的HIV的细胞缓存并消除它们，必须面对挑战：1)从临床获得的血浆样本中采样的淋巴细胞的变化是否反映了人体深层隔室，特别是包括中枢神经系统(CNS)在内的非淋巴器官中发生的情况，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)CNS和/或深层器官隔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，应该选择性地作为消除的目标？3)CNS和其他身体深层隔室中HIVint的细胞缓存是否均匀分布，并具有特定的细胞类型？特别值得关注的是，单核吞噬细胞中的潜伏期，包括体内广泛存在的组织组织细胞，尚不清楚。这些细胞是中枢神经系统(CNS)和其他非淋巴组织的关键储存库。这些基本问题很难在临床上解决，因为获取人体组织标本是必要的。这项研究计划将利用感染艾滋病毒的特征良好的受试者的组织标本来确定已整合到人类基因组中的艾滋病毒DNA的细胞缓存，从而可能导致艾滋病毒在体内的潜伏。一个目标是定义中枢神经系统中的艾滋病毒DNA池。第二个目标将在人体其他深层组织中产生类似的数据。这些数据将有助于实地瞄准携带潜伏病毒的细胞，以便将其根除。

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.