Description of Research Expertise

Research Interests
All double-stranded DNA viruses which replicate in the nucleus must induce mechanisms that alter the cell's metabolic and synthetic environment to permit the synthesis of large amounts of viral proteins, the replication of viral DNA, and the production of new virions. As the infection proceeds, the virus must control apoptosis and cellular stress responses induced by the viral infection. Such stress responses are initiated by nutrient deprivation, hypoxia, and synthetic stress, e.g. endoplasmic reticulum stress and the unfolded protein response (UPR). These stress responses, which are induced to allow the cell to recover from adverse conditions, may not be advantageous to the virus; for example, they often result in inhibition of translation. Thus, it is expedient for the virus to establish mechanisms to counteract the inhibitory effects of stress responses.
Over the past 10 years my lab has been at the forefront of studying how DNA viruses alter cellular signaling in order to manipulate stress responses for the advantage of the infection. We have learned much about how human cytomegalovirus (HCMV) alters the unfolded protein response, and how it maintains mTOR kinase activity despite the induction of stress reponses that would normally inhibit it. Our ongoing studies deal with determining how HCMV maintains mTOR kinase activity under conditions of oxidative stress and amino acid deprivation.
We have also begun studies which focused on cellular metabolism and how HCMV infection affects it. Specifically, we are examining the uptake and utilization of glucose, which is altered during infection such that glucose is used biosynthetically instead of catabolically. To accomplish this HCMV induces the analperotic utilization of glutamine; indeed virus production becomes dependent on glutamine. How the virus mediates these significant changes is an intense area of study.
Our cumulative data suggest that the pathogenic effects of these alterations could implicate HCMV and related DNA viruses as subtle cofactors in many maladies. For example, many of the pathways we have found to be altered by HCMV are also altered during oncogenesis. Additional the HCMV-mediated alterations of metabolism are very similar to what occurs in many tumor cells. While not suggesting that HCMV is a frank transforming agent, it is possible that the effects of HCMV (and similar viruses) on cellular pathways serve as one step among several that promote transformation, as suggested by the Knudson "multi-hit” hypothesis.