AIDS dementia is a progressive neurological disease that affects a significant portion of HIV-infected persons. However, the pathogenesis of neurological disease development in HIV-infected persons is not well understood. While human studies have improved our understanding of the interaction of HIV with the central nervous system (CNS), an appropriate animal model system would enable a detailed examination of the mechanisms of induction of AIDS dementia. A major gap in knowledge concerns the evolution of virus in the CNS and the role of genotype in the induction of neurologic disease. We have identified a simian immunodeficiency virus (SIV) isolate, derived from a sooty mangabey, that is highly neuropathogenic in infected pigtailed macaques. This virus, termed SIVsmmFGb, also induces clear neurologic dysfunction in these animals. We believe that this virus provides an excellent system for investigating the basis of HIV-1 induced neurologic disease. The central hypothesis to be evaluated is that there is genetic selection and evolution of SIV that occurs in the CNS, separate from that in the periphery, which is directly related to the development of neurologic disease. Specific hypotheses to be investigated are: 1) genotypic selection occurs after virus enters the CNS; 2) viral evolution in 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 aims, we will compare the selection and evolution of SIV genotypes in the CNS and the lymphoid system. Investigations both early and late during infection in SIVsmmFGb-infected macaques will enable a determination of what virus enters the CNS, how it is related to the virus in the periphery and what virus persists after the primary immune response. In an effort to determine if genotypic compartmentalization occurs, macaques infected with SIVsmmFGb will undergo behavioral/cognitive testing and magnetic resonance spectroscopy scanning to localize effects of virus on the CNS. These areas will then be examined for SIV genotype. Finally, along with genotypic change comes phenotypic change. We will investigate the ability of viruses isolated at various times after infection to replicate in macrophages and microglia. This will enable us to determine if viral evolution in the CNS is accompanied by viral fitness to grow in the CNS. Finally, we will investigate the evolution of the ability of these viruses to induce the production of neurotoxins in CNS derived cells.
