Protein/Nucleic Acid Interactions Controlling Retroviral

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The success of antiviral therapies will require a detailed knowledge of proteins involved in the replication, assembly, and infectivity of HIV-1 and HIV-2. Central to these processes is the enzyme reverse transcriptase (RT), which has been a leading target for antiviral drugs for over a decade. Since RT-mediated replication of the HIV RNA genome is a multistep process, dissecting and understanding each event at the molecular level will have the consequence of expanding the repertoire of therapeutic targets. Moreover, current evidence suggests RT may not work alone in replicating the HIV genome, but rather recruits additional viral proteins. A better understanding of the "communication" between these accessory proteins and RT can therefore offer additional avenues for intervention. Research in the RT Biochemistry Section exploits recombinant DNA technology to accurately recapitulate steps in HIV replication and evaluate their sensitivity to antiviral agents, using the enzymes of HIV-1, HIV-2, and their counterparts from closely related viruses. Furthermore, since alterations in RT structure result in the rapid acquisition of drug resistance and failure of antiviral therapies, it is important to understand the exact nature of these subtle alterations. Thus, in addition to a biochemical analysis, the laboratory currently applies bioconjugate and mass spectrometric approaches in an effort to obtain high-resolution structural information on both wild-type and mutant variants of this highly versatile enzyme.