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，影响很大一部分hiv感染者。然而，艾滋病毒感染者神经系统疾病发展的发病机制尚不清楚。虽然人类研究提高了我们对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使我们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的进化和基因型在神经系统疾病诱导中的作用。我们已经鉴定出一种猴免疫缺陷病毒（SIV）分离物，来源于黑白眉猴，在感染的尾猴中具有高度神经致病性。这种被称为SIVsmmFGb的病毒也会在这些动物中诱发明显的神经功能障碍。我们相信这种病毒为研究HIV-1诱导的神经系统疾病的基础提供了一个很好的系统。待评估的中心假设是SIV的遗传选择和进化发生在中枢神经系统，与外周神经系统不同，这与神经系统疾病的发展直接相关。需要研究的具体假设有：1)病毒进入中枢神经系统后发生基因型选择；2)中枢神经系统的病毒进化不同于淋巴组织；3)基因型区隔化发生在中枢神经系统，与神经系统疾病的发生有关；4) SIV在中枢神经系统基因型进化的同时，也发生表型进化，促进了中枢神经系统的生长，也促进了神经系统疾病的发展。为了实现这些目标，我们将比较SIV基因型在中枢神经系统和淋巴系统中的选择和进化。在感染sivsmmffg的猕猴中进行感染早期和晚期的调查，将能够确定哪种病毒进入中枢神经系统，它与外周病毒的关系，以及哪种病毒在初次免疫反应后持续存在。为了确定是否发生基因型区隔化，将对感染SIVsmmFGb的猕猴进行行为/认知测试和磁共振波谱扫描，以确定病毒对中枢神经系统的局部影响。然后将对这些地区进行SIV基因型检查。最后，伴随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病毒在中枢神经系统中的进化是否伴随着病毒在中枢神经系统中生长的适应性。最后，我们将研究这些病毒诱导中枢神经系统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.