Genetics of Neuropathogenic SIV Infection

描述(申请人提供)：艾滋病痴呆症是一种进行性神经系统疾病，影响到很大一部分艾滋病毒感染者。然而，HIV感染者神经系统疾病的发病机制还不是很清楚。虽然人类研究提高了我们对艾滋病毒与中枢神经系统(CNS)相互作用的理解，但合适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。知识上的一个主要差距涉及中枢神经系统中病毒的进化以及基因在诱发神经疾病中的作用。我们已经确定了一种猴免疫缺陷病毒(SIV)分离株，它来自一种煤烟芒果，在受感染的辫尾猕猴中具有高度的神经致病性。这种病毒被称为SIVsmmFGb，也会导致这些动物明显的神经功能障碍。我们认为，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。需要评估的中心假说是，存在发生在中枢神经系统的SIV的遗传选择和进化，与周围的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后发生基因选择；2)CNS中的病毒进化不同于淋巴组织；3)CNS中发生基因区隔，与神经系统疾病的发生有关；4)随着CNS中SIV的基因进化，表型进化也发生，这有助于CNS的生长，也有助于神经系统疾病的发展。为了达到这些目标，我们将比较中枢神经系统和淋巴系统中SIV基因类型的选择和进化。对感染SIVsmmFGb的猕猴进行感染早期和晚期的调查将有助于确定什么病毒进入中枢神经系统，它与周围的病毒是如何相关的，以及什么病毒在初级免疫反应后仍然存在。为了确定是否发生了基因区划，感染了SIVsmmFGb的猕猴将接受行为/认知测试和磁共振光谱扫描，以定位病毒对中枢神经系统的影响。然后将对这些地区进行SIV基因型检查。最后，伴随着基因类型变化的是表型变化。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中生长的适宜性。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进化。

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.