GENETICS OFNEUROPATHOGENIC SIV INFECTION

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。艾滋病性痴呆是一种进行性神经系统疾病，影响了很大一部分艾滋病毒感染者。一个主要的知识缺口涉及病毒序列在诱导神经系统疾病中的作用。我们已经鉴定出一种猴免疫缺陷病毒（SIV）分离物，称为SIVsmmFGb，来源于黑白眉猴，它在尾猴中具有高度神经致病性。中心假设是SIV的遗传选择和进化发生在中枢神经系统，而不是发生在淋巴系统，这与神经系统疾病的发生直接相关。具体来说，1)病毒进入中枢神经系统后发生基因型选择；2)病毒进化是中枢神经系统不同于淋巴组织；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。为了验证这些假设，我们比较了SIV基因型在感染后的早期（7天）和早期（2个月）在中枢神经系统和淋巴系统中的选择和进化。目前的数据表明，在大脑和淋巴系统之间，以及可能在大脑的不同结构中，存在一种初始的区隔化序列。我们已经证明，从sivsmmfgb感染的猕猴的大脑中提取的SIV的独特分子克隆只能感染巨噬细胞。这种病毒已被接种到两只长尾猕猴身上，以研究这种不寻常病毒的影响。迄今为止，这些动物没有表现出疾病发展的迹象，也没有纠正导致病毒不寻常特征的突变。

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 there is an initial compartmentalization of sequences both between the brain and lymphoid system, as well as possibly within separate structures of the brain. 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.