Neurological syndromes have frequently been described in patients with acquired immunodeficiency syndrome (AIDS). Recent reports on the isolation of infectious human immunodeficiency virus (HIV) from cerebrospinal fluid (CSF) and brain tissues of patients with AIDS and the detection of HIV DNA in the brain strongly suggest that HIV is directly responsible for some of the neurological manifestations. The type(s) of brain- derived cells which can be infected by HIV is under active investigation; however, the possibility that a neurotropic variant strain of the virus might be responsible for neural infection remains to be determined. Several HIV isolates from the CSF and brain tissue of AIDS patients have been cultured in our laboratory. In some cases, the HIV from lymphocytes of the same individual were also obtained. When some of the isolates were inoculated onto brain-derived cell cultures, they productively infected glial cells, particularly those with astrocyte markers. Thus, an in vitro assay to study neurotropism is available. We propose to characterize, at the molecular level, two central nervous system (CNS)-derived HIV isolates and one corresponding lymphocyte-derived HIV isolate. These HIV can be distinguished by their replicating properties in different cells. We shall clone their proviral forms from genetic libraries of virus-infected cellular DNA. Molecular clones of these viruses will be subjected to restriction endonuclease analysis and the resulting DNA fragments will be isolated and sequenced. AT the biological level, differences in the ability of these three HIV isolates to infect human cell lines, particularly those derived from brain will be further studied. To map the viral sequences encoding the determinant(s) for cell type tropism, we shall construct recombinant viral DNA genomes using biologically active molecular clones of HIV with different cell tropisms. Infectious recombinant HIV's, recovered from transfection of human lymphoid cells with recombinant DNA's will then be tested for their ability to infect different cell types. Data obtained from this proposed study will help determine (1) the extent of genomic variations between isolates from the brain and lymphocytes of the same individual, (2) whether """"""""neurotropic HIV"""""""" is a subtype of the AIDs virus, and (3) the region(s) of the HIV genome that governs tropism for different cell types.
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