We initially intended to develop an animal model for cytomegalovirus (CMV)-associated disease by chemically immunosuppressing three rhesus macaques. Our immunosuppression regimen (anti-rhesus CD3 MAb, cyclosporin and cytoxan) was designed to mimic immunosuppression in human organ transplantation recipients that develop CMV-associated disease. Unfortunately, none of the macaques demonstrated reactivation in the peripheral blood compartment as defined by PCR amplification of DNA derived from peripheral blood mononuclear cells. During the past year, we experimentally infected two of these three with a simian immunodeficiency virus (SIV) isolate in an attempt to reactivate CMV in the peripheral blood compartment. From these in vivo studies the following observations were made. 1) Experimental infection of rhesus macaques with SIV EvT3 did not result in the reactivation of CMV in the peripheral blood compartment. Studies in HIV-infected patients have shown that human CMV load in the peripheral blood compartment increases prior to clinical signs of CMV-associated diseases. Thus, our studies suggest that SIV infection alone is insufficient at stimulating widespread CMV dissemination. 2) SIV infection was associated with localized CMV disease that caused significant morbidity resulting in the termination of one macaque. Thus, conditions that mediate widespread CMV dissemination need to be determined. We believe there are two possibilities to potentially explain the lack of widespread CMV reactivation in the two macaques. First, an additional stimulus may be required for CMV reactivation. In solid organ and bone marrow transplants, the organ or bone marrow is derived from an allogenic donor. Hence, a concomitant allogenic stimulus may be required for CMV reactivation, such as a blood transfusion. HIV patients receive blood transfusions during the course of their disease. The second possibility is that the immunosuppression was not severe enough for reactivation, as the CD8+ T cell remained stable in the macaques. Cytotoxic T lymphocytes are known to play a significant role in maintaining CMV in both humans and rhesus macaques. We believe that additional treatments, such as anti-CD8 monoclonal antibodies, should provide the stimulus for widespread CMV reactivation. FUNDING Center-supported project PUBLICATIONS Swanson R, Bergquam E, Wong SW. Characterization of rhesus cytomegalovirus genes associated with anti-viral susceptibility. Virology 240:338-348, 1998.
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