GENETICS OFNEUROPATHOGENIC SIV INFECTION

这个子项目是众多研究子项目之一

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. he unusual charAIDS dementia is a progressive neurological disease that affects a significant portion of HIV-infected persons, even in the presence of anti-retroviral therapy. A major gap in knowledge concerns the evolution of virus in the CNS and the role of viral genotype in the induction of neurologic disease. We have identified a simian immunodeficiency virus (SIV) isolate, termed SIVsmmFGb that is highly neuropathogenic in infected pigtailed macaques. The central hypothesis to be evaluated is that there is separate genetic selection and evolution of SIV that occurs in the CNS, which is directly related to the development of neurologic disease. Specific hypotheses investigated are: 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 development of neurologic disease. SIV sequences derived from the SIVsmmFGb virus stock as well as from four areas of the brain and from several lymph nodes of both sets of macaques are currently being cloned and analyzed. In the V1 region of Env, we found eight (8) different groups of virus present in the uncloned SIVsmmFGb stock. When compared with sequences derived from the tissues of infected macaques, data from the first group of six macaques is suggestive of specific viral sequences responsible for initial neuroinvasion; where specific groups are present in the CNS, but not in the periphery. A unique molecular clone of SIV derived from the brain of a SIVsmmFGb-infected macaque can only infect macrophages and maintains this phenotype even in macaques infected with the virus for over two years. acteristics of the virus.