ABSTRACT
Because of its key role in the retroviral life cycle, the reverse transcriptase (RT) enzyme of the human immunodeficiency virus (HIV) is an important target for the development of antiviral agents that suppress viral replication. Retroviral reverse transcription is a complex process carried out by the HIV-encoded RT enzyme that displays DNA polymerase activities on both DNA and RNA templates as well as an RNase H activity that degrades the transcribed genomic RNA. Both the polymerase and RNase H activities of HIV-1 RT are essentially required to convert the genomic RNA into a double-stranded DNA molecule that is later integrated into the host genome [1]. However, all currently approved RT inhibitors used in the clinic are directed against the polymerase active center [2]. Blocking of the RT-associated RNase H activity has until now been demonstrated only in vitro or in cell-free assays [3-5]. Two categories of drugs have been developed to antagonize the polymerase activity of HIV RT: nucleoside analog RT inhibitors (NRTIs) that compete with cellular dNTPs for binding and incorporation
and non-nucleoside analog RT inhibitors (NNRTIs) that act as noncompetitive antagonists of the enzyme. In addition, phosphonoformic acid (PFA, foscarnet), a pyrophosphate analog, is capable of inhibiting a broad spectrum of DNA polymerases including HIV-1 RT, but its clinical use is hampered by several factors, including the lack of an orally bioavailable form [6].
