VIRAL COFACTORS IN HIV INFECTION AS TARGETS FOR THERAPY

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We proposed to identify specific targets for antiviral therapy by investigating the viral determinants of pathogenesis by the human immunodeficiency virus (HIV). There is abundant molecular, virologic, and epidemiologic evidence that viral cofactors, particularly Epstein-Barr virus (EBV) and cytomegalovirus (CMV), may be involved in the pathogenesis of AIDS related complex (ARC) and AIDS. We therefore plan to examine the relationship of these viruses to HIV infected cells. Antiviral therapy may then be aimed at the virus identified as a probable cofactor in the progression of HIV infection as well as at HIV itself. We plan to perform in situ hybridization and immunohistochemical staining to analyze tissues and cells from individuals who are HIV seropositive and well, have ARC, have AIDS, and controls. We aim to determine if cells demonstrating expression of HIV also show expression of EBV or CMV or border on such cells. Numerous samples of lymphoid tissue, bone marrow, brain, and peripheral blood lymphocytes will be examined using in situ hybridization to detect HIV RNA and immunohistochemical staining to detect EBV and CMV antigen; in addition tissues will be examined using in situ hybridization to detect CMV RNA and immunohistochemistry to detect expression of HIV antigen. We shall also examine the spatial relationship of cells showing expression of these viruses. In tissues derived from people without opportunistic infections, expression of CMV or EBV in the same cells or cells neighboring those expressing HIV will add in vivo evidence to the already existing in vitro evidence that these viruses may act as cofactors in the progression of HIV infection. In addition, we shall perform a series of experiments to assay whether CMV or EBV can potentiate the production of HIV in vitro; if in vitro potentiation is demonstrated, we shall test to see if this effect can be blocked by agents that inhibit CMV or EBV replication.