Genetics of Simian Immunodeficiency Virus Encephalopathy

描述（由申请人提供）：在广泛使用高效抗逆转录病毒疗法（HAART）之前，大约20%的HIV感染患者发展为HIV相关性痴呆（HAD）。HAART明显降低了HAD的发病率，但随着HIV感染者寿命的延长，其患病率或较轻的认知障碍的患病率可能会上升。慢病毒性脑炎也经常发生在感染猴免疫缺陷病毒（SIV）的猕猴中，SIV是HIV最重要的动物模型。后来分析病毒基因型的研究也确定，无论分析的基因组的哪一部分，同一个体的脑、脾和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，也记录了CNS内的区域变化。然而，目前尚不清楚（1）大脑基因型是否是适应性选择的结果，由于大脑相对于免疫系统的“特权”位置而减少的免疫约束，或者是由于分区群体的遗传漂变。或者，它可能是所有这些因素的汇合。还不确定的是（2）脑内发生的变异体是否可能特别具有神经致病性，以及（3）脑内的变异体是否构成潜在的潜伏感染库，能够在HAART治疗后重新接种体循环。我们建议使用猴免疫缺陷病毒（SIV）感染恒河猴来解决这些问题，该模型概括了HIV感染的大部分特征，包括CNS疾病。我们提出三个具体目标。在第一个目标中，我们将扩增和克隆来自患有SIV脑炎的猕猴的env基因组DNA，将基因组DNA与从单个多核巨细胞扩增的SIV RNA进行比较，并测定包膜的功能和它们的神经致病潜力。在第二个具体目标中，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CNS内区室化的时间过程。在第三个具体目标中，我们将跟踪以前的结果，这些结果表明一些细胞携带SIV序列长达2年。这些实验将有助于阐明基因隔离在SIV脑炎发展中的作用，并由此扩展到人类。

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.