Genetics of Neuropathogenic SIV Infection

描述（由申请人提供）：艾滋病痴呆是一种进行性神经系统疾病，影响了相当一部分艾滋病毒感染者。 然而，HIV感染者神经系统疾病发展的发病机制还不清楚。虽然人类研究已经提高了我们对HIV与中枢神经系统（CNS）相互作用的理解，但适当的动物模型系统将能够详细检查艾滋病痴呆的诱导机制。一个主要的知识缺口涉及病毒在中枢神经系统中的演变和基因型在神经系统疾病诱导中的作用。我们已经确定了一种猴免疫缺陷病毒（SIV）分离株，来源于一只白眉猴，在感染的猪尾猕猴中具有高度神经致病性。这种称为SIVsmmFGb的病毒也在这些动物中诱导明显的神经功能障碍。我们相信，这种病毒提供了一个很好的系统，调查的基础上HIV-1诱导的神经系统疾病。要评估的中心假设是，存在发生在CNS中的SIV的遗传选择和进化，与外周中的SIV分离，这与神经系统疾病的发展直接相关。需要研究的具体假设是：1）病毒进入CNS后发生基因型选择; 2）CNS中的病毒进化与淋巴组织不同; 3）CNS中发生基因型区室化，并与神经系统疾病的发展有关;沿着SIV在CNS中的基因型进化，也发生表型进化，其促进CNS中的生长并且还促进神经疾病的发展。为了实现这些目标，我们将比较中枢神经系统和淋巴系统中SIV基因型的选择和演变。在SIVsmmFGb感染的猕猴感染期间的早期和晚期的研究将能够确定什么病毒进入CNS，它如何与外周中的病毒相关，以及什么病毒在初次免疫应答后持续存在。为了确定是否发生基因型区室化，感染SIVsmmFGb的猕猴将接受行为/认知测试和磁共振波谱扫描，以定位病毒对CNS的影响。然后检查这些区域的SIV基因型。最后，沿着基因型变化而来的是表型变化。我们将研究感染后不同时间分离的病毒在巨噬细胞和小胶质细胞中复制的能力。这将使我们能够确定CNS中的病毒进化是否伴随着病毒在CNS中生长的适应性。最后，我们将研究这些病毒诱导CNS衍生细胞产生神经毒素的能力的演变。

DESCRIPTION (provided by applicant): AIDS dementia is a progressive neurological disease that affects a significant portion of HIV-infected persons. However, the pathogenesis of neurological disease development in HIV-infected persons is not well understood. While human studies have improved our understanding of the interaction of HIV with the central nervous system (CNS), an appropriate animal model system would enable a detailed examination of the mechanisms of induction of AIDS dementia. A major gap in knowledge concerns the evolution of virus in the CNS and the role of genotype in the induction of neurologic disease. We have identified a simian immunodeficiency virus (SIV) isolate, derived from a sooty mangabey, that is highly neuropathogenic in infected pigtailed macaques. This virus, termed SIVsmmFGb, also induces clear neurologic dysfunction in these animals. We believe that this virus provides an excellent system for investigating the basis of HIV-1 induced neurologic disease. The central hypothesis to be evaluated is that there is genetic selection and evolution of SIV that occurs in the CNS, separate from that in the periphery, which is directly related to the development of neurologic disease. Specific hypotheses to be investigated are: 1) genotypic selection occurs after virus enters the CNS; 2) viral evolution in the CNS is distinct from the lymphoid tissue; 3) genotypic compartmentalization occurs in the CNS and is related to the development of neurologic disease; and 4) along with genotypic evolution of SIV in the CNS, phenotypic evolution also occurs, which facilitates growth in the CNS and also facilitates development of neurologic disease. To address these aims, we will compare the selection and evolution of SIV genotypes in the CNS and the lymphoid system. Investigations both early and late during infection in SIVsmmFGb-infected macaques will enable a determination of what virus enters the CNS, how it is related to the virus in the periphery and what virus persists after the primary immune response. In an effort to determine if genotypic compartmentalization occurs, macaques infected with SIVsmmFGb will undergo behavioral/cognitive testing and magnetic resonance spectroscopy scanning to localize effects of virus on the CNS. These areas will then be examined for SIV genotype. Finally, along with genotypic change comes phenotypic change. We will investigate the ability of viruses isolated at various times after infection to replicate in macrophages and microglia. This will enable us to determine if viral evolution in the CNS is accompanied by viral fitness to grow in the CNS. Finally, we will investigate the evolution of the ability of these viruses to induce the production of neurotoxins in CNS derived cells.