Derek A. Jacobs, PhD

Research Title: Protein-Protein Interactions in HCMV

Project Summary: Human Cytomegalovirus (HCMV) is a member of the betaherpesvirus family that establishes a lifelong latent infection in its host. This latent state is maintained by a multitude of viral and cellular factors which act by mechanisms not fully understood. Dr. Jacobs has focused on an example of a mechanism for silencing the major immediate-early promoter involving the viral protein UL138 and the cellular protein CtBP1. Two parallel approaches were used: direct protein-protein interactions between UL138 and CtBP1, and biochemical changes to CtBP1 due to UL138 activity. The first approach involves using a structure/function mutagenic strategy to determine the region of UL138 that is required for the interaction with CtBP1. This approach was assisted by the existence of a chimpanzee CMV (CCMV) ortholog of UL138 which shares 50% similarity to the HCMV protein. Another ortholog of UL138 was discovered in Rhesus Cytomegalovirsus (RhCMV) called Rh166, and this protein was used to try to determine which specific portion of UL138 is critical for its function. Once the portion of the UL138 protein which is required for this interaction is known, the precise mechanism of action will be determined more easily. A second, complimentary approach to understanding the mechanism of action between UL138 and CtBP1 will take advantage of various known biochemical properties of CtBP1 and assay for those properties to determine if they are affected by treatment with UL138. These interactions may prove to be novel and sufficiently unique to allow for the development of new antiviral drugs targeting this specific interaction. Drugs of this nature could target the latent reservoir of HCMV in infected patients and prevent reactivation events by mimicking the action of UL138 on CtBP1, thereby introducing a new treatment paradigm for HCMV.