HIV-1 reverse transcriptase and antiviral drug resistance. Part 1

• HIV-1 RT is targeted by 13 anti-AIDS drugs.
• Mutations in RT confer resistance to RT inhibitors.
• Structures have revealed various functional/conformational states of RT.
• New NNRTIs are adaptive, which enhances their resilience to resistance mutations.

HIV-1 reverse transcriptase (RT) contributes to the development of resistance to all anti-AIDS drugs by introducing mutations into the viral genome. At the molecular level, mutations in RT result in resistance to RT inhibitors. Eight nucleoside/nucleotide analogs (NRTIs) and five non-nucleoside inhibitors (NNRTIs) are approved HIV-1 drugs. Structures of RT have been determined in complexes with substrates and/or inhibitors, and the structures have illuminated different conformational and functional states of the enzyme. Understanding the molecular mechanisms of resistance to NRTIs and NNRTIs, and their complex relationships, may help in designing new drugs that are periodically required to overcome existing as well as emerging trends of drug resistance.

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