GENETICS OFNEUROPATHOGENIC SIV INFECTION

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 艾滋病痴呆是一种进行性神经系统疾病，影响到相当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。我们已经确定了一种猴免疫缺陷病毒（SIV）分离株，称为SIVsmmFGb，来源于一种高神经致病性的长尾猕猴。 中心假设是，存在发生在CNS中的SIV的遗传选择和进化，与淋巴系统中的SIV分离，这与神经系统疾病的发展直接相关。 具体而言，1）基因型选择发生在病毒进入CNS后; 2）病毒进化是CNS与淋巴组织不同; 3）基因型区室化发生在CNS中，并与神经系统疾病的发展有关;和4）沿着CNS中SIV的基因型进化，也发生表型进化，其促进CNS中的生长，也促进神经系统疾病的发展。 为了解决这些假设，我们比较了SIV基因型的选择和演变在中枢神经系统和淋巴系统在感染后立即早期（7天）和早期（2个月）。 目前的数据表明，虽然病毒对CNS的初始入侵并不限于特定序列，但CNS和淋巴系统内的序列存在初始区室化。 我们已经证明，一个独特的分子克隆的SIV来自大脑的SIVsmmFGb感染的猕猴只能感染巨噬细胞。 这种病毒已被接种到两只长尾猕猴，以研究这种不寻常的病毒的影响。 迄今为止，这些动物没有显示出疾病发展的迹象，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.