Mutation L210W of HIV-1 reverse transcriptase in patients receiving combination therapy - Incidence, association with other mutations, and effects onthe structure of mutated reverse transcriptase

Mutation L210W of HIV-1 reverse transcriptase (RT) is one of the six main m utations that confer in vivo resistance to zidovudine. Surprisingly, this m utation has received scant appraisal and its contribution to the genotypic resistance to nucleoside analogs is not well understood. The aim of this st udy was: (1) to study the frequency of mutation L210W in a large collection of HIV-1 sequences (2,049 samples, including 395 DNA and 1,654 RNA sequenc es) from patients receiving combination therapy, and (2) to analyze its ass ociation with the other mutations that confer resistance to zidovudine. A m utation at codon 210 (mainly L210W) was found in 647 (32%) of the 2,049 seq uences analyzed. Only 43 (<7%) of these 647 genomes were also mutated at co don 70 (p < 10(-5)). In contrast, 98% of these 647 sequences were also muta ted at codon 215 (essentially T215Y/F), and 94% at codon 41 (mainly M41L). These data showing a close association between L210W, T215Y/F, and M41L, an d a mutual exclusion between K70R and L210W, were confirmed by analyzing th e sequences stored in the HIV-1 sequences available through the Stanford HI V RT and Protease Database. Follow-up studies demonstrated that L210W appea red always after T215Y/F. This observation is consistent with crystallograp hic studies which suggested that the aromatic side chain of Trp 210 could s tabilize the interaction of Phe/Tyr215 with the dNTP-binding pocket. This m olecular cross-talk between amino acid chains occurs nearby the conserved A sp113 residue. Since the lateral chain of Arg70 may also interact with Asp1 13, this is likely to create a sterical hindrance around this residue. Thus , the R-->K reversion of codon 70 may represent a compensatory mechanism al lowing a functional rearrangement of the dNTP-binding pocket in the mutated RT. Copyright (C) 2000 National Science Council, ROC and S. Karger AG, Bas el.