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

Abstract

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 revealed 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.

Analysis of the Zidovudine Resistance Mutations T215Y, M41L, and L210W in HIV-1 Reverse Transcriptase

“…When the polymerase adds a dinucleotide monophosphate (dNMP) to the 3= end of the primer strand, inorganic pyrophosphate (PP i ) is released. Immediately after incorporation of a nucleotide, the 3= end of the primer ϩ1 strand temporarily resides in the N site; translocation moves the end of the primer from the N site to the P site, which allows the cycle to be repeated (1)(2)(3)(4)(5)(6).…”

“…Structural and modeling studies have shown that the T215Y mutation is one of two (with K70R) primary AZT resistance mutations (2)(3)(4)(5). AZT-resistant HIV-1 RT transfers the AZTMP from the end of the DNA primer to the ␥-phosphate of the ATP, forming a dinucleoside tetraphosphate and producing a free 3=-OH group at the end of the primer strand (Fig.…”

“…This type of mutation (collectively referred to as "exclusion mutations") can be either active, if, for example, there is a direct steric clash between the amino acid substitution and the incoming inhibitor, e.g., when the M184V/I mutations cause a steric clash with the oxathiolane ring of 3TC triphosphate (3TCTP), or passive, in which differences in the interactions of the normal dNTPs and the NRTITPs with the mutant RT favor the incorporation of the normal dNTPs over the analog (e.g., Q151M and K65R) (3)(4)(5).…”

“…The AZTMP moiety is removed from the end of the primer by using an ATP-dependent pyrophosphorolysis mechanism that is related to, but distinct from, polymerization reactions run in reverse (2)(3)(4)9). ATP-dependent excision removes the AZTMP from the 3= end, freeing the viral primer strand so that DNA synthesis can continue.…”

Potent Inhibitors Active against HIV Reverse Transcriptase with K101P, a Mutation Conferring Rilpivirine Resistance

“…Resistance-associated mutations (RAMs) within or near the non-nucleoside binding pocket reduce the potency of first generation NNRTIs such as efavirenz. 9 Rilpivirine represents a new class of flexible diarylpyrimidne (DAPY) inhibitors that maintains activity against several RT resistant variants with K103N, Y181C, Y188L, and L100I mutations. 11−13 As more combination treatments such as Complera 14 include rilpivirine in antiretroviral regimens, less frequent variants of RT may emerge that contain mutations at the K101 position.…”