Human immunodeficiency virus reverse transcriptase and antiretroviral therapy

RTs are used in recombinant DNA technology to synthesize complementary DNA (cDNA) from messenger RNA (mRNA) and are key elements in the development of transcriptomics. Efficient, inexpensive and reliable methods providing complete, representative and strand-specific RNA-seq libraries are needed in many biomedical applications, and RTs play a central role in those analyses. We plan to study HIV recombination, and specifically the molecular basis of strand transfer and nontemplated nucleotide addition with two major objectives: (i) to understand the role of relevant RT residues in strand transfer and recombination, through the analysis of the effects of amino acid substitutions that are predicted to have an impact in strand transfer and nontemplated nucleotide addition; and (ii) to obtain an RT devoid of strand transfer activity that ideally should also show high fidelity of DNA synthesis and remarkable catalytic efficiency at elevated temperatures (above 65ºC).

In addition, we are interested in therapeutic targets for HIV, emphasizing on the role of the viral enzymes (protease, RT and integrase). HIV RT plays a pivotal role in the replication of the viral genomic RNA. Understanding the role of different residues in RT function (mainly DNA polymerase activity, but also ribonuclease H (RNase H) function and reverse transcription initiation) should help us to design novel strategies for treating HIV infection. We have ongoing collaborations with medicinal chemistry labs interested in the development and characterization of RNase H inhibitors.  It should be noted that drugs targeting RNase H activity have not been approved for clinical use so far.