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Reverse transcriptase (RT) of HIV-1 remains an important target in current treatments of HIV-1 infection. Clinically available inhibitors of HIV-1 RT include nucleoside analog RT inhibitors and non-nucleoside RT inhibitors. Nucleoside analog RT inhibitors compete with the natural dNTP substrate and act as chain terminators, while non-nucleoside RT inhibitors bind to an allosteric pocket, inhibiting polymerization noncompetitively. In addition to these two classes of approved drugs, there are a number of RT inhibitors that target the enzyme in different ways. These include nonobligate chain terminators, nucleotide-competing RT inhibitors, pyrophosphate analogs and compounds that inhibit the RT-associated RNase H activity. Here, we review the mechanisms of action associated with these compounds and discuss opportunities and challenges in drug discovery and development efforts.

Members of the ribonuclease H (RNase H) family of enzymes (EC 3.1.26.4), which are found in nearly all organisms, are endoribonucleases that specifically hydrolyze the phosphodiester bond of RNA in a RNA–DNA hybrid. In retroviruses such as HIV-1, the RNase H activity is part of reverse transcriptase, the enzyme that converts the viral ssRNA into dsDNA suitable for integration into the host cell genome. In HIV-1, RNase H plays an essential role in various stages of reverse transcription, and it has been known for 20 years that inhibiting RNase H activity renders HIV noninfectious. However, the development of potent and selective antagonists of HIV RNase H has made surprisingly slow progress, and so far no RNase H inhibitor is in clinical trial, rendering this enzyme an important, but as yet underexplored, drug target. The recently described crystal structure of human RNase H in complex with a RNA–DNA hybrid provides new insight into the mechanism of HIV RNase H activity, with the potential to unveil new niches for therapeutic intervention. The current status of RNase H screening efforts is reviewed here.