Mechanisms of immune evasion by HHV-6 and HHV-7 U21

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DESCRIPTION (provided by applicant): Human herpesvirus-6 and -7 (HHV-6,-7) are two closely related beta-herpesviruses that infect over 90% of the population. These opportunistic viruses do not usually cause serious illness in healthy people, but in immunocompromised individuals, these viruses can reactivate and cause life-threatening encephalitis, CMV disease, and hepatitis. HHV-6 is also considered a possible viral causative agent of Multiple Sclerosis. Like all other herpesviruses, HHV-6 and -7 persist or remain latent in their hosts throughout life. In so doing, herpesviruses have evolved numerous strategies to escape detection by the immune system. Many viruses, including most members of the herpesvirus family, have evolved mechanisms to interfere with viral antigen presentation by class I MHC molecules as a means of escaping detection by cytotoxic T lymphocytes. HHV- 7 encodes one such gene product, U21, that binds to and diverts class I MHC molecules to a lysosomal compartment. The focus of this proposal is to determine the mechanism employed by HHV-7 U21 to escape detection by the immune system. The function of the closely related U21 gene product in HHV-6 will also be examined. Recent work has shown that the lumenal domain of U21 is critical for diversion of class I molecules to the lysosomal compartment. Several strategies will be employed to ascertain the mechanism of the lumenal domain of HHV-7 U21. 1) the biochemical and morphological nature of the compartment to which class I molecules are diverted will be examined, 2) the identity of cellular proteins responsible for diversion of class I molecules to this compartment will be determined. 3) the effect of U21 and the cellular proteins responsible for diversion will be examined in HHV-7 infected cells and 4) the domains of the class I molecule essential for U21 binding will be mapped. The long term goal of this project is to understand the mechanisms by which HHV-6 and -7 evade detection by the immune system. Revelation of the mechanisms by which these opportunistic viruses evade the immune system will not only contribute to the understanding of these viruses and their pathogenesis, but also to the understanding of the basic underlying principles of lysosomal trafficking. Ultimately, the knowledge gained from understanding how these molecules function to downregulate the immune response may lead to the identification of potential therapeutic targets for treatment of these opportunistic infections, as well as for the treatment of autoimmune disorders.