The objectives of the Virology Core are to elucidate the role of HIV- 1 in the development of central nervous system (CNS) impairment, to identify HIV-1-specific determinants predictive of CNS dysfunction, and to determine the importance of human cytomegalovirus (CMV) on the development of HIV-1-related CNS disease. The findings of the Virology Core will be integrated in the HNRC data base, which will enable correlations with findings of the other research cores and specific projects. Additionally, cerebrospinal fluid (CSF), peripheral blood mononuclear cells and plasma specimens, viral isolates, and nucleic acids (including PCR amplified products) will be stored in the HNRC specimen bank and made available to other investigators for further virologic investigations.
The specific aims of the Virology Core are: (1) To identify virologic markers and kinetics of HIV-1 replication which are predictive of HIV-1-related CNS disease. We hypothesize that HIV-1 load as determined by quantitative RNA, and decreased antiretroviral sensitivity as determined by phenotypic and genotypic analyses of HIV-1 isolates and nucleic acid from CSF will correlate with the presence and development of neurocognitive impairment. Additionally, we will examine the kinetics of HIV-1 replication within the CSF, and correlate these findings with replication kinetics in plasma and the presence of neurocognitive impairment: (2) To determine the pathogenetic significance of enhanced HIV-1 replication in macrophages cocultured with endothelial cells in the development of CNS impairment. The hypothesis to be tested is that HIV-1 strains with the greatest enhanced replication in macrophage-endothelial cell cultures will be most likely to enter the CNS and be correlated with the development of neurocognitive impairment. Additionally, we propose to develop strategies to block macrophage/binding to brain microvascular endothelial cells such that HIV-1 replication in the brain will be decreased, and thus, reduce the incidence of HIV-1-related CNS impairment; (3) To determine the role of CMV in the development of CNS disease in HIV-1-infected persons and to define the importance of antiviral resistance in persons who develop CMV- related CNS disease. We hypothesize that as HIV-1-infected persons survive for prolonged periods with low CD4+ lymphocyte counts that viruses other than HIV-1, particularly CMV, will become increasingly important copathogens contributing to the development of neurocognitive impairment. Additionally, we hypothesize that as oral ganciclovir prophylaxis is used to prevent CMV disease that resistant strains of CMV will become an important cause of CNS disease. For these studies, we will perform qualitative and quantitative PCR assays to monitor patients participating in the proposed CMV study. Additionally, clinical isolates and DNA obtained from the CSF of these study participants will be evaluated for phenotypic and genotypic resistance to antivirals (ganciclovir, foscamet and HPMPC) most often used to treat HIV-1-infected persons With CMV disease. The findings of the Virology Core will improve the understanding of HIV-1 pathogenesis and enable the design of treatment studies directed toward the prevention of CNS dysfunction in persons identified to be at highest risk for developing abnormalities.
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