INTERACTION OF HTLV-III/LAV WITH HEPATITIS B VIRUS

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The acquired immunodeficiency syndrome (AIDS) is a fatal immunoregulatory disorder which is characterized by an irrevesible, quantitative and functional depletion of the helper/inducer T-cell subset. Although there is substantial evidence to implicate a human T-cell leukemia/lymphoma virus (HTLV-III/LAV) as the primary etiologic agent of this disorder, several characteristics of the disease suggest that one or more infectious agents may function as cofactors in the development of the disease. One virus which has been implicated in a cofactor role is the hepatitis B virus. The long-term objective of this proposal is to define the role which HBV plays in the development of AIDs. The specific aims of this study are to determine, by comprehensive molecular analysis, the prevalence of HBV DNA in peripheral blood mononuclear cells (PBMC) from HTLV-III/LAV infected subjects who display a broad range of symptoms from mild and transient to severe and prolonged disease. The nucleic acid hybridization results in PBMC will be correlated with existing HBV serologic markers (including serum-associated HBV DNA) and with HTLV-III/LAV isolation data. Followup of apparently healthy blood donors, who have antibody to HTLV-III/LAV, will be conducted to determine the relationship between PBMC-associated HBV DNA and the progress of the disease. Subsequent evaluations will be made to determine which specific mononuclear cell subset(s) contains the HBV-related DNA and in situ hybridization will be performed to establish the percentage of HBV DNA positive cells in each cell subset(s). The physical state, genomic content and subcellular localization of PBMC-associated HBV DNA also will be defined. To evaluate the level of viral gene expression which is occurring in HBV DNA positive mononuclear cells, PBMC from HTLV-III/LAV infected patients will be examined for HBV-specific RNA by RNA/DNA hybridization and analyzed by radioimmunoassay and the Western blot technique for the presence of viral-encoded antigens. Finally, an attempt will be made to establish an in vitro model using cocultivation and transfection methodology to determine whether HBV infection of lymphoid cells can influence the replicative or cytopathic potential of HTLV-III/LAV. Establishing the molecular and biologic events of HBV multiplication within PBMC will be of crucial importance in elucidating the mechanism by which HBV may be serving as a cofactor in HTLV-III induced disease.