My laboratory works on two distinct groups of pathogenic viruses, i.e., the herpesvirus and retrovirus families. In the case of the herpesviruses, our research is focused on the role of virally encoded microRNAs in viral replication and pathogenesis. Herpesviruses, almost uniquely among viruses, have been found to encode numerous microRNAs, many of which were first identified by my group. Herpesviruses use microRNAs to downregulate the expression of specific cellular and viral mRNAs in infected, particularly latently infected, cells. Our research is particularly focused on the human γ-herpesviruses KSHV and EBV and on the α-herpesviruses HSV-1 and HSV-2. In the case of KSHV and EBV, we have obtained data showing that virally encoded microRNAs can disrupt regulation of the cell cycle by targeting cellular tumor suppressor proteins, such as the cyclin dependent kinase inhibitor p21. In this way, these viral miRNAs play a key role in promoting the known oncogenic potential of KSHV and EBV. In the case of HSV-1 and HSV-2, our data indicate that the viral microRNAs help to maintain these viruses in a latent state in infected neurons, at least in part by downregulating viral immediate early proteins that activate entry into the lytic viral life cycle. We are actively pursuing the possibility that chemotherapeutic intervention targeting these α-herpesvirus microRNAs might disrupt viral latency and hence provide an approach to curing patients persistently infected by these viral pathogens.
Our research in the retrovirus field is focused on cellular proteins that confer innate resistance to retroviral infection and also retrotransposon mobility. We are primarily working on the APOBEC3 family of resistance factors, which plays a key role in regulating the species tropism of retroviruses, and on mechanisms developed by viruses to resist inhibition by the APOIBEC3 proteins expressed in their cognate host species. We are also interested in the TREX proteins, which appear to act by degrading single-stranded reverse transcripts in the cytoplasm. Together, these projects are targeting multiple questions at the interface of viral pathogenesis and host antiviral immunity.