Human Cytomegalovirus-Associated Immunosuppression Is Mediated Through Interferon-α

Human cytomegalovirus (HCMV) infections are commonly associated with a generalized immunologic hyporesponsiveness. The present study was designed to evaluate the potential mechanisms of HCMV-associated immunosuppression. In our initial experiments, monocytes in peripheral blood mononuclear cells (PBMCs) exposed to cell-free HCMV appeared morphologically less differentiated than monocytes in PBMCs exposed to a mock preparation. These morphologic changes were closely correlated with a decrease in monocyte oxidative activity and occurred under noncytopathic conditions. HCMV-associated suppression of monocyte differentiation did not require virus replication, occurred in PBMCs from either HCMV seropositive or seronegative donors, and required HCMV interaction with the nonadherent cells. An HCMV-induced soluble factor was found to not only reproduce the identical changes in purified monocytes but to inhibit the phagocytic activity of these cells. Additionally, the HCMV-induced factor accounted for a generalized defect in the ability of PBMCs to proliferate in response to mitogens and recall antigens. In subsequent experiments, interferon-alpha (IFN-alpha) was identified as the soluble factor involved in these immunosuppressive effects. Thus, PBMCs, when exposed to HCMV, produce a soluble factor, identified as IFN-alpha, that appears to be an important mediator of immunosuppression associated with HCMV infection.