Our research focuses on the complex host-virus interactions that result in viral persistence. Progress in understanding latent programs of persistence have been impeded by the inherent complexity of the viruses and that paucity of adequate model systems. Herpesviruses are extraordinary for their ability to coexist with their host by establishing life-long latent infections. Latency is defined as a reversibly quiescent state during which viral gene expression and replication is highly restricted. Our laboratory studies cytomegalovirus or CMV, one of eight human herpesviruses.
CMV is remarkable in that it persists latently in 60-99% of the population, generally in the absence of disease in the immunocompetent host. Reactivation of CMV from latency poses life-threatening disease risks in immunocompromised individuals, including transplant, AIDS and cancer patients. CMV infection is also the leading cause of infectious disease-related birth defects, affecting ~1% of live births in the US. The health cost of the latent coexistence of CMV is just beginning to emerge in an association to age-related pathologies including atherosclerosis, immune senescence and frailty. The key to eradicating CMV lies in understanding latency in order to ultimately develop novel antiviral strategies targeting latently infected cells. Our studies aim to define the molecular basis of persistence by defining viral and cellular determinants important to viral persistence and the mechanisms by which these determinants function in relevant cell models. In turn, our work will provide critical insights into how CMV assimilates into and impacts human biology.
Viral Determinants of Latency. CMV encodes >170 genes, most of which are dispensable for replication of the virus in cultured cells. We hypothesize that the remaining “non-essential” genes are essential for modulating infection and persistence in cell types relevant to infection in the host. Using a reverse genetics approach, we defined UL138 as a suppressor of productive HCMV replication in CD34+ HPCs, a postulated site of latency (Goodrum et al., Blood 2007, Petrucelli et al., J. Virol 2009). The protein encoded by UL138, pUL138, is dispensable for viral replication in fibroblasts, but required for the establishment of an experimental latency in HPCs infected in vitro. pUL138 is encoded within a polycistronic locus encoding three novel proteins, pUL133, pUL135 and pUL136, in addition to pUL138 (Grainger, et al., J Virol 2010). While the UL133-UL138 locus is dispensable for replication in fibroblasts, it augments replication in endothelial cells and suppresses replication in CD34+ HPCs. Therefore, the locus as a whole can exert positive (endothelial), negative (HPCs) or no (fibroblasts) effect on virus replication, indicating a unique role of this locus in mediating context-dependent outcomes of infection (Umashankar et al., PLoS Pathog 2011). My research program’s greatest proportion of effort is focused on understanding how the novel proteins encoded within the UL133-UL138 locus contribute individually and collectively to viral persistence in relevant cell types. Intriguingly, the locus encodes proteins that both promote and repress viral replication suggesting the existence of a molecular switch controlling productive and latent states of infection.
Epigenetics. We are interested in the cellular mechanisms underlying latency. Upon viral entry, the viral genome is translocated to the nucleus, where it is chromatinized. The epigenetic regulation of the viral chromosome is important to the outcome of viral infection. Our research will define the epigenetic signature of the viral genome in various cell types relevant to HCMV infection and determine how nuclear architecture is changed by persistence of the virus. This work will contribute to our understanding of how viral gene expression is regulated during infection.