Innate immunity senses intracellular pathogens and induces the expression of cellular genes with antiviral functions. Most if not all viruses encode proteins that inhibit innate immunity during productive, lytic infections, but the role of innate immunity during viral latency is underappreciated and understudied. Latency permits human cytomegalovirus (HCMV) to colonize its hosts for their lifetime by avoiding immune detection and clearance. During latency, the levels of lytic (productive) phase HCMV proteins such as IE1 (Immediate Early 1) are kept extremely low (or completely absent) because the promoter that drives its expression, the Major Immediate Early Promoter (MIEP) is transcriptionally silenced by heterochromatin. IE1 is a transcription factor that promotes progression through the viral lytic phase and is a target of cytotoxic T cells. Therefore, keeping IE1 protein levels low or absent protects latently infected cells from immune surveillance and restricts reactivation events until the proper stimulus is sensed. We published that the viral UL138 protein silences IE1 transcription during latency by inhibiting the recruitment of lysine- specific demethylases (KDMs) to the MIEP that otherwise remove repressive epigenetic histone methylations to activate transcription. Our preliminary data indicates this occurs, in part, through a suppression of cellular innate immune pathways. Here we propose to determine how UL138-mediated evasion of cellular innate immunity contributes to the establishment and maintenance of HCMV latency, with a particular focus on viral epigenetics and the transcriptional silencing of IE1.
Human cytomegalovirus infects almost everyone. It causes birth defects and disease in people sick with cancer, AIDS, and those undergoing organ transplants. It also seems to exacerbate cardiovascular diseases, to adversely affect the ability of the elderly to fight off other infectious diseases, and may be directly related to human glioblastoma multiforme brain tumors. HCMV can hide in the body in a latent state and reactivate at any time to cause disease and to spread from person to person. This work will study how HCMV establishes this latent state, with the hopes of identifying ways to fight the virus with antiviral drugs.
