GENETICS OFNEUROPATHOGENIC SIV INFECTION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 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。关于病毒序列在诱发神经系统疾病中的作用，知识上的一个主要差距。我们已经鉴定出一种猴免疫缺陷病毒(SIV)分离株，命名为SIVsmmFGb，它来自于一种在辫尾猕猴中高度神经致病的煤烟曼加比病毒。中心假说是，SIV存在发生在中枢神经系统的遗传选择和进化，与淋巴系统的遗传选择和进化是分开的，这与神经系统疾病的发展直接相关。具体地说，1)病毒进入中枢神经系统后发生基因选择；2)病毒进化是指中枢神经系统与淋巴组织不同；3)中枢神经系统发生基因区隔，与神经系统疾病的发生有关；4)随着SIV在中枢神经系统的基因进化，表型进化也会发生，这有利于中枢神经系统的生长，也有助于神经系统疾病的发展。为了解决这些假设，我们比较了感染后即刻早期(7天)和早期(2个月)中枢和淋巴系统中SIV基因型的选择和进化。目前的数据表明，虽然病毒对中枢神经系统的初始入侵并不局限于特定的序列，但在中枢神经系统和淋巴系统内存在着序列的初始划分。我们已经证明了来自SIVsmmFGb感染猕猴大脑的SIV的一个独特的分子克隆只能感染巨噬细胞。这种病毒已经接种到两只辫子猕猴体内，以研究这种不寻常的病毒的影响。到目前为止，这些动物还没有表现出疾病发展的迹象，也没有纠正导致病毒异常特征的突变。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. AIDS dementia is a progressive neurological disease that affects a significant portion of HIV-infected persons. A major gap in knowledge concerns the role of viral sequences in the induction of neurologic disease. We have identified a simian immunodeficiency virus (SIV) isolate, termed SIVsmmFGb, derived from a sooty mangabey, which is highly neuropathogenic in pigtailed macaques. The central hypothesis is that there is genetic selection and evolution of SIV that occurs in the CNS, separate from that in the lymphoid system, which is directly related to the development of neurologic disease. Specifically, 1) genotypic selection occurs after virus enters the CNS; 2) viral evolution is 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 hypotheses, we compared the selection and evolution of SIV genotypes in the CNS and the lymphoid system at immediate early (7 days) and early times (2 months) after infection. Current data suggests that while the initial invasion of the CNS by virus is not limited to specific sequences, there is an initial compartmentalization of sequences within the CNS and the lymphoid system. We have shown that a unique molecular clone of SIV derived from the brain of a SIVsmmFGb-infected macaque can only infect macrophages. This virus has been inoculated into two pigtailed macaques to investigate the effects of such an unusual virus. To date, the animals have shown no signs of disease development and have not corrected the mutation responsible for the unusual characteristics of the virus.