Genetics of Simian Immunodeficiency Virus Encephalopathy

猿猴免疫缺陷病毒脑病的遗传学

• 批准号: 6682733
• 负责人: Francisco Gonzalez-Scarano
• 金额: $ 48.21万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6682733
• 关键词: AIDS dementia complex; AIDS therapy; Macaca mulatta; SDS polyacrylamide gel electrophoresis; apoptosis; central nervous system; electron microscopy; encephalitis; gene expression; genotype; immunocytochemistry; lymphocyte; neuropathology; polymerase chain reaction; simian immunodeficiency virus; virus genetics

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.

描述（由申请人提供）：在广泛使用高度活性的抗逆转录病毒疗法（HAART）之前，大约20％的HIV感染患者发展了与HIV相关的痴呆症（HAT）。 Haart显然降低了HAT的发病率，但由于HIV感染的人的寿命更长，因此其患病率或不太严重的认知障碍可能会上升。慢病毒脑炎也持续发生在感染猿猴免疫缺陷病毒（SIV）的猕猴中，这是HIV最重要的动物模型。在后面分析了病毒基因型的研究还表明，无论分析了分析的基因组的部分，大脑内部的病毒与同一个体的脾脏和其他外周组织之间存在明显的遗传差异。在某些情况下，也已经记录了中枢神经系统内的区域变化。但是，尚不清楚（1）由于适应性选择而出现大脑基因型是由于免疫系统中大脑的“特权”位置引起的免疫学约束，还是由于分室群体的遗传漂移而引起的。另外，它可能是所有这些因素的汇合。也不确定（2）大脑内发生的变体是否可能特别是神经病，以及（3）大脑内的变体是否构成潜在的潜在潜在感染库，能够在与HAART治疗后能够重新播种系统循环。我们建议使用恒河猕猴的Simian免疫缺陷病毒（SIV）感染来解决这些问题，该模型概括了包括CNS疾病在内的HIV感染的大多数特征。我们提出了三个具体目标。在第一个目的中，我们将从猕猴中扩增和克隆ENV基因组DNA，将基因组DNA与从单个多核巨细胞中扩增的SIV RNA进行比较，并在功能上分析信封在功能上及其神经疾病的潜力。在第二个特定目的中，我们将分析感染了SIV分子克隆的猕猴中的血液，脑脊液和其他组织，以确定中枢神经系统内SIV的时间过程。在第三个特定目的中，我们将跟进先前的结果，表明某些细胞含有SIV序列长达2年。这些实验将有助于阐明遗传隔离在SIV脑炎发展中的作用，并在其人类对应物中扩展。