Antiviral responses of host mediated S-nitrosylation of viral proteins.

Human cytomegalovirus (HCMV) is a common pathogen that has infected a majority of the human population. While symptoms of HCMV are generally resolved in immunocompetent individuals, the virus remains for the lifetime within the host as a latent infection is established in the hematopoietic stem cells. HCMV has co- evolved with humans and as such, the virus as adapted to undermine host cell antiviral responses. How HCMV undermines these responses is not fully known. Our research has found that an understudied protein modification, S-nitrosylation, plays a role in how HCMV interacts with the antiviral response. We found that viral proteins critical for efficient lytic replication are post translationally modified with nitric oxide groups and that the resulting modifications alter the viral proteins ability to limit antiviral responses. We propose to mechanistically investigate how these modifications impact HCMV protein functions and to identify the impact of S-nitrosylation on HCMV replication. Completion of the aims above will contribute significantly to our knowledge the regulation of biological functions of critical viral factors as well as identify the mechanism by which viruses weaken host defenses against infection. This work will lay the foundation in identifying novel therapeutic targets for a pathogen that lacks a vaccine or a cure.