GENETICS OF NEUROPATHOGENIC SIV INFECTION

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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. HIV-associated dementia is a progressive neurological condition that affects a significant proportion of HIV-infected people, and occurs as a result of viral replication in the brain. HIV enters the brain (neuroinvasion) through the transmigration of infected blood monocytes during normal immune surveillance of central nervous system (CNS) tissues. Although HIV-infected monocytes can probably be found in the circulation of all seropositive individuals, not all HIV-positive people develop HIV encephalitis or HIV-associated dementia. This suggests that viral determinants may be important in determining whether HIV infection becomes established in the brain; however, the role that viral genetic elements play in neuroinvasion and the pathogenesis of HIV encephalitis are unknown. We have developed a nonhuman primate model of HIV encephalitis that uses an isolate of SIV (SIVsmmFGb) that is highly neuropathogenic in pig-tailed macaque monkeys. Timed necropsies have been performed on 12 pig-tailed macaques, collecting CSF, plasma, a variety of brain specimens, and lymphoid tissues. Six of these animals were necropsied during the acute stage of infection (5 to 7 days post inoculation) and six animals were necropsied two months after inoculation. SIV envelope gene sequences will be analyzed from viruses isolated from the CNS and peripheral lymphoid tissues at acute and 2 month post-inoculation time points. These sequences will be compared with envelope sequences in the original inoculum to investigate whether CNS isolates harbor unique envelope determinants that confer a neuroinvasive phenotype. To aid in this investigation, we have used in situ hybridization to screen CNS and lymphoid tissues from all six of the acutely infected animals for productively infected cells. This procedure has facilitated the cloning experiments by identifying regions of the brain containing productively infected cells.