HCMV US2 & US11 Inhibition of MHC Class II Presentation

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DESCRIPTION (provided by applicant): 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 benign but causes serious disease in immunocompromised and immunosuppressed patients. The present trend toward more transplantation will cause continued escalation of HCMV disease. In newborn children, HCMV causes birth defects and neurological dysfunction and may account for a substantial number of children with disabilities. In AIDS, HCMV frequently causes retinitis seen in late stages of the disease and this seriously decreases the quality of life. HCMV retinitis is less frequent with HAART, although it is not clear whether HAART will keep HIV in decline and retinitis will likely continue to be a major problem. Cellular immune responses are critical to controlling HCMV. However, the virus can persist and even reinfect seropositive individuals that have preexisting and robust immunity. In part, this may relate to a substantial panel of HCMV immune evasion or modulation proteins. Understanding how these proteins promote resistance to immune recognition and effector strategies will have important implications for producing a vaccine, something that is critically needed. We described effects of HCMV US2 and US3 on MHC class II antigen presentation to CD4+ T cells. US2 causes degradation of MHC proteins, apparently by triggering a fundamental and important cellular process termed ER-associated degradation (ERAD). Our research will focus on the molecular mechanisms of US2-mediated degradation and ERAD. US2 and a related protein US11 are among the best molecular handles on ERAD. Our recent work has also provided new insights into how the MHC class II pathway normally functions to present HCMV antigens, by an endogenous, rather than exogenous or extra cellular, pathway. We will extend these studies of HCMV class II antigen presentation and grapple with how US2, US3 and US11 function in the context of HCMV-infected cells, in part by characterizing rhesus CMV homologues of US2, US3 and US11.