Human T-cell lymphotropic virus type-III/lymphadenopathy- associated virus (HTLV-III/LAV) has been implicated as the primary etiological agent of acquired immune deficiency syndrome (AIDS). AIDS, a disease characterized by opportunistic infections and specific malignancies, results primarily from an underlying immunological dysfunction due to the selective destruction of the OKT4+ lymphocyte subpopulation after infection by HTLV-III/LAV. In addition to complications resulting from HTLV-III/LAV immune dysfunction, several distinct neurological syndromes (encephalopathy, spinal cord degeneration, meningitis, and chronic peripheral neuropathy) have been recognized and recent evidence has indicated that HTLV-III/LAV may also be directly involved in these neuropathological processes. The overall objective of the proposed research will be to use an in vitro system to examine the interaction of HTLV- III/LAV with the human nervous system, utilizing neural cells isolated from central and peripheral nervous system tissue of aborted human fetal material.
The specific aims of the proposed research are to examine (i) the HTLV-III/LAV genome and the production of HTLV-III/LAV RNA, protein, and infectious virus during acute virus infection of human fetal neural cell populations and during the subsequent transition from acute to persistent or latent infection; (ii) the identification of those human neural cell- types refractile to HTLV-III/LAV infection as well as those susceptible to HTLV-III/LAV infection with or without subsequent cell death; (iii) the effect of acute and persistent or latent HTLV- III/LAV infection on selected human fetus neural cell functions; (iv) activation of HTLV-III/LAV-specific gene expression and productive replication in persistently or latently infected neural cell populations; and (v) the chemo-and immunotherapeutic modification of HTLV-III/LAV-specific gene expression during acute and persistent or latent infection of neural cell populations. Scientific disciplines involved will include neurobiology and molecular neurovirology with experimental application of human neural cell culture, DNA- and RNA-specific hybridization technology, protein analysis with neural cell-and HTLV-III/LAV- specific monoclonal antibodies, fluorescence-activated flow cytometry, and hybridoma technology. The long-range goal will be to provide information essential to understanding the molecular neuropathogenesis of HTLV-III/LAV infection in humans, and ultimately, in the control of human disease caused by HTLV-III/LAV.
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