Human cytomegalovirus (HCMV) is a ubiquitous virus that infects a substantial fraction of the U.S. population, leading to lifelong persistent or latent infections. HCMV is normally quite benign but causes serious problems in immunocompromised or immunosuppressed patients, especially after bone marrow and solid organ transplantation where the virus causes pneumonia, graft rejection, and disseminated diseases. In AIDS, HCMV causes retinitis, frequently seen in late-stages of the disease, and this seriously decreases the quality of life for AIDS patients. HCMV-induced retinitis was common, in 20-55% of AIDS patients, before Highly Active Anti Retroviral Therapy (HAART). Since HAART, retinitis and other HCMV-induced diseases have declined dramatically. It is not clear whether HAART will continue to keep HIV in decline and, if HIV rebounds, HCMV-induced retinitis will likely reestablish itself as a major problem. Moreover, the present trend toward increased numbers of bone marrow and solid tissue transplants will cause continued escalation of HCMV disease. Cellular immune responses are critical to controlling HCMV replication and spread, especially following virus reactivation from latency. However, HCMV uses a panel of proteins to evade the host immune system, viral proteins that block recognition by natural killer cells and T lymphocytes. The applicant has recently reported an HCMV protein, US2, which is the first-described viral inhibitor of the MHC class II antigen presentation pathway that signals virus infection to CD4+ T cells. These observations provide an important new insight into how HCMV can hide out or persist in MHC class II pathway functions in a virus-infected cell, to present endogenous rather than exogenous antigens. In the studies proposed herein he would characterize the effects of US2 in macrophages and endothelial cells and determine the molecular basis for how US2 inhibits the class II pathway.
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