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Research
Labs: Mark
Ayer Muesing, Ph.D.
Integrase (IN) belongs to an ancient group of enzymes, the polynucleotidyl-transferases, a superfamily of proteins that, in part, are responsible for carrying out the nucleic acid transactions critical to the propagation of a variety of small, self-contained and semi-autonomous mobile DNA elements that exist within and between cells. Both the catalytic and structural features essential for function have been highly conserved throughout evolution from the recombinases and transposases of the primordial insertion elements/transposons found in bacteria to the integrases of the retrotransposons and retroviruses that persist in higher cells. Yet the type of catalysis performed by this class of enzymes is not confined exclusively to these small DNAs. Indeed, a related set of cellular proteins is required for the generation of both B and T cell receptor diversity in lymphocytes, critical to the formation of the adaptive immune response. Very few viral families that infect eukaryotes encode and/or utilize an integrase-like protein within their respective life cycles. However, retroviruses, the subfamily to which the immunodeficiency viruses belong, require absolutely the catalytic properties (and perhaps other functions) of the integrase protein for the establishment and maintenance of their genomic information—activities essential for their sustained propagation. Integrase-mediated recombination or integration of the viral DNA into the host chromosomal DNA at once provides not only a suitable environment for the efficient expression of viral genetic information leading to the efficient manufacturing of progeny virus but also provides a mechanism by which the viral genome is stably (and irreversibly) transferred to all subsequent daughter cells upon host DNA replication and cell division. Thus, integrase is a pivotal molecule during the first half of the HIV life cycle affecting such diverse processes as reverse transcription, viral nuclear import and the integration and expression of the viral genome. Given that these processes are indispensable for viral growth, our laboratory is focused on a more through understanding of the diverse functions provided by this remarkable protein. We place particular emphasis on host cell factors that act in conjunction with integrase to coordinate the processes that occur between viral entry and steps leading up to, and including the completion of proviral integration. The use of isolated biochemical and genetic systems provide the tools necessary to understand the molecular details that underlie these obligatory processes. Results obtained through these means can then be recapitulated in a more physiologic environment, by assessing the success of viral infection with precise measurement of the stepwise progression through the early events of the HIV-1 life cycle with specific assay. Areas of
Research
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