This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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.
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