The major goals of this proposal are to elucidate interactions between human cytomegalovirus (CMV) and human immunodeficiency virus type I (HIV-1) in the natural history of AIDS development, progression, and neoplasia. There is substantial evidence that the vast majority of patients with AIDS are infected with both viruses. Interactions may take several forms (a) additive or synergistic immunosuppression or cytopathology (b) activation of one virus by the other (c) alteration of cell surface receptors to one virus by infection with the other (d) phenotypic mixing (e) viral recombination. Such interactions may, in turn, result in altered viral tropism and enhancement of neoplastic transformation. CMV-HIV-1 interactions in vitro and in vivo will be explored. Cells dually infected will be studied for progeny CMV/HIV pseudotypes or recombinants by a variety of techniques including cross-neutralization, immune electron microscopy, and altered tropism determinations. Attempts will be made to rescue an envelope-deficient HIV-1 molecular construct from cells carrying it by use of a CMV envelope. Rescue analysis will be assessed by use of selective markers (resistance to mycophenolic acid), polymerase chain reaction assays of secondarily infected fibroblasts, and detection of HIV-1 antigen expression. Alterations in viral cell tropism resulting from interactions will be explored. In vivo interactions between CMV and HIV-1 will also be explored. Dually infected patients will have specimens (blood, semen) examined for CMV/HIV pseudotypes or recombinants. Autopsy brain and retinal specimens will also be studied. The tropism of CMV/HIV pseudotypes or recombinants derived from these sources will be evaluated on various cell targets, as will their capacity to induce cytopathic or transforming infections in such cells.
