Genetics of Simian Immunodeficiency Virus Encephalopathy

描述(申请人提供)：在广泛使用高效抗逆转录病毒疗法(HAART)之前，大约20%的艾滋病毒感染患者出现了艾滋病毒相关性痴呆(HAD)。HAART明显降低了HAD的发病率，但随着感染艾滋病毒的人寿命延长，其患病率或不太严重的认知障碍的发病率可能会上升。慢病毒脑炎也持续发生在感染了猴免疫缺陷病毒(SIV)的猕猴身上，SIV是HIV最重要的动物模型。后来对病毒基因类型进行了分析的研究也证实，无论分析的基因组部分如何，藏在大脑、脾和同一人的其他外周组织中的病毒之间存在明显的遗传差异。在某些情况下，还记录了CNS内部的区域差异。然而，尚不清楚(1)大脑的基因分型是由于适应性选择的结果，还是由于大脑相对于免疫系统的‘特权’地位而减少的免疫约束，还是由于划分人群的遗传漂移。或者，它可能是所有这些因素的汇合。还不确定(2)大脑内发育的变异是否可能特别引起神经病变，以及(3)大脑内的变异是否构成潜在的潜在感染宿主，能够在使用HAART治疗后重新播撒体循环。我们建议用猴免疫缺陷病毒(SIV)感染恒河猴来解决这些问题，这是一种概括了包括中枢神经系统疾病在内的HIV感染的大多数特征的模型。我们提出了三个具体目标。在第一个目标中，我们将从患有SIV脑炎的猕猴中扩增和克隆SIV基因组DNA，将基因组DNA与从单个多核巨细胞中扩增出的SIV RNA进行比较，并对包膜进行功能分析和神经致病潜能的检测。在第二个特定目标中，我们将分析感染SIV分子克隆的猕猴的血液、脑脊液和其他组织，以确定SIV在中枢神经系统内区域化的时间进程。在第三个具体目标中，我们将跟踪先前的结果，这些结果表明一些细胞含有SIV序列长达2年之久。这些实验将有助于阐明基因隔离在SIV脑炎发展中的作用，进而在人类脑炎中也是如此。

DESCRIPTION (provided by applicant): Prior to the widespread use of highly active anti-retroviral therapy (HAART) roughly 20% of HIV-infected patients developed HIV-associated dementia (HAD). HAART has clearly decreased the incidence of HAD, but its prevalence, or that of less severe cognitive disorders, may rise as individuals with HIV infection live longer. Lentiviral encephalitis also occurs consistently in macaques infected with simian immunodeficiency virus (SIV), the most important animal model for HIV. Studies that have analyzed viral genotypes at later points have also established that there is clear genetic divergence between viruses harbored within the brain and the spleen and other peripheral tissue of the same individual, regardless of the portion of the genome that is analyzed. In some instances regional variation within the CNS has also been documented. However it is not clear (1) whether the brain genotypes arise as a result of adaptive selection, decreased immunological constraints due to the brain's 'privileged' position with respect to the immune system, or are due to genetic drift of a compartmentalized population. Alternatively it could be a confluence of all these factors. It is also uncertain (2) whether the variants developing within the brain may be particularly neuropathogenic, and (3) whether the variants within the brain constitute a potential reservoir of latent infection, able to re-seed the systemic circulation after treatment with HAART. We propose to address these questions using simian immunodeficiency virus (SIV) infection of rhesus macaques, a model that recapitulates most of the features of HIV infection including CNS disease. We propose three specific aims. In the first aim, we will amplify and clone env genomic DNA from macaques with SIV encephalitis, compare the genomic DNA with SIV RNA amplified from individual multinucleated giant cells, and assay the envelopes functionally and for their neuropathogenic potential. In the second specific aim, we will analyze blood, cerebrospinal fluid and other tissues in macaques infected with a molecular clone of SIV, to determine the time course of compartmentalization of SIV within the CNS. In the third specific aim we will follow up on previous results indicating that some cells harbor SIV sequences for periods as long as 2 years. These experiments will help clarify the role of genetic sequestration in the development of SIV encephalitis, and by extension, in its human counterpart.