The Role of Human Cytomegalovirus Protein UL135 in Virus Replication, Latency, and Reactivation

Abstract

Human cytomegalovirus (CMV) is a ubiquitous herpesvirus that infects the majority of the world’s population. CMV can establish a latent infection, enabling the lifelong persistence of CMV infection and effectively evading the immune system and antiviral drugs. We have characterized the protein product of UL135 (pUL135), and discovered that pUL135 drives viral replication and is necessary for viral reactivation from latency, counteracting the latency-promoting effects of another CMV protein, pUL138. The functions of pUL135 and pUL138 proteins are antagonistic, epistatically linked, and the balance between pUL135 and pUL138 regulates viral infection and latency. Through the use of proteomic screens, we have identified and disrupted interactions of pUL135 with cellular proteins Abi-1 and CIN85; we discovered that interactions are necessary for viral reactivation from latency. pUL135 and its interactions with Abi-1 and CIN85 influence the levels of EGFR on the cell and alter the dynamics of EGFR trafficking within the cell. This work investigates the various roles and mechanisms by which UL135 serves as a mediator of CMV infection.