Cytomegalovirus (CMV) modulates host immune function. Heightened interest in this aspect of CMV biology is attributed to the realization that CMV may serve as a cofactor in the pathogenesis of HIV. The role of CMV in AIDS pathology may be: 1) its immunosuppressive properties, and/or 2) its ability to upregulate cytokines known to enhance HIV replication. the murine model of CMV-induced immune alterations affords the opportunity to address this potential role of CMV. These studies will focus on CMV- macrophage interactions, as infection of macrophages eliminates the ability of these antigen-presenting cells to stimulate T cells while causing overexpression of monokines. This proposal will test the hypothesis that CMV infection of SV40-transformed macrophages and expression of viral gene products in these cells perturbs 1) antigen-presenting functions by inhibiting a) peptide processing and/or b) major histocompatibility antigen expression; and 2) accessory functions by altering monokine production. Viral-induced changes in processing of T antigen will be identified by use of synthetic minigenes and epitope-specific CTL clones. To detect alterations in MHC expression, promoter activity and levels of mRNA and intracellular protein will be quantitated. Effects of the virus on newly- synthesized H-2Kd and beta2m expressed by vaccinia virus will also be assessed. To test effects of CMV on macrophage accessory functions, the frequency of SV40-immune lymph node cells producing monokines in vivo will be compared between CMV-infected and non-infected mice. Frequency of T helper cells responding in vitro to monokines from infected and non- infected macrophages will be compared. The effects of virus infection on promoter activity, production, and secretion of monokines known to be important to CTL regulation and HIV replication (IL-1, IL-6, transforming growth factor, and tumor necrosis factor) will be assessed. Finally, the role of CMV gene expression in the above immunological parameters will be determined. Various CMV mutants and transfected gene products will be tested for their effects on antigen presentation, and expression of MHC molecules and monokines. This proposal combines molecular and cellular techniques with biological assays to define mechanisms of CMV-induced immune alterations.
