Lab Research Focus
The research in my laboratory is directed towards understanding, at the molecular level, virus-host cell interactions. We have focused our studies on a key step in the replication of retroviruses. During replication, retroviruses undergo a process in which the plus strand RNA genome is converted to a DNA intermediate; this process is called reverse transcription and is catalyzed by a viral encoded enzyme, reverse transcriptase. All known retroviruses use a cellular tRNA as a primer for reverse transcriptase. However, different retroviruses use different, but specific, tRNA as their primers for reverse transcription. For example, HIV-1 exclusively uses tRNALys,3 for reverse transcription, while murine leukemia virus (MuLV) and human T-cell leukemia virus (HTLV-1) use tRNAPro.
Research in my laboratory is focused on understanding why retroviruses, such as HIV-1, specifically select tRNALys.3 for reverse transcription. For these studies, we use contemporary techniques in molecular biology to construct HIV-1, MuLV and HTLV-1 which are forced to use tRNA primers different from the wild type virus. Comparison of the replication in vitro and in vivo using animal model systems of the mutant and wild type viruses provides insights into the importance of the specific tRNA in viral pathogenesis.
A second area of interest is to understand how the virus selects the specific tRNA. The normal function of tRNAs in protein synthesis makes the availability of free tRNAs for the virus to use reverse transcription primers scarce within infected cells. How the virus captures specific tRNAs for initiation of reverse transcription necessitates developing a greater understanding of the trafficking of tRNAs in normal and virus infected cells. To study this problem, we have developed a unique complementation system for HIV-1 that allows manipulation of the tRNA primer used for replication. We are using this system to delineate the important elements of the tRNA required for selection and use as a tRNA primer.
Finally, we are using the information gained from these studies in the design of new approaches to disrupt the selection process that retroviruses use to capture tRNAs. Ultimately, we will use this information to develop therapeutics designed to disrupt retrovirus (e.g. HIV-1) replication.
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