We propose to investigate 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), hepatitis B virus (HBV), 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 to determine if a cofactor relationship may exist in vivo. We plan to perform in situ hybridization and immunohistochemical staining on 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, HBV, or CMV or border or such cells. Numerous samples of lymphoid tissue, bone marrow, brain, and peripheral blood lymphocytes will be examined using the combined technique of in situ hybridization to detect HIV RNA and immunohistochemical staining to detect HIV RNA and immunohistochemical staining to detect EBV, HBV, or CMV antigen; in addition tissues will be examined using combined in situ hybridization to detect CMV or HBV RNA and immunohistochemical staining to detect expression of HIV antigen. In tissues derived from people without opportunistic infections, expression of CMV, HBV, 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.
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