- 作者: Nouara Yahi; Catherine Tamalet; Christian Tourres; Natacha Tivoli; Jacques Fantini
- 作者服務機構: UF SIDA, CHRU de la Timone, and Institut Mediterraneen de Recherche en Nutrition, Faculte des Sciences St-Jerome, Marseille, France
- 中文摘要: --
- 英文摘要: Mutation L210W of HIV-1 reverse transcriptase (RT) isone of the six main mutations that confer in vivo resis-tance to zidovudine. Surprisingly, this mutation has re-ceived scant appraisal and its contribution to the geno-typic resistance to nucleoside analogs is not well under-stood. The aim of this study was:(1) to study the frequen-cy of mutation L210W in a large collection of HIV-1sequences (2,049 samples, including 395 DNA and 1,654RNA sequences) from patients receiving combinationtherapy, and (2) to analyze its association with the othermutations that confer resistance to zidovudine. A muta-tion at codon 210 (mainly L210W) was found in 647 (32%)of the 2,049 sequences analyzed. Only 43 (<7%) of these647 genomes were also mutated at codon 70 (p<10-5).In contrast, 98% of these 647 sequences were also mu-tated at codon 215 (essentially T215Y/F), and 94% atcodon 41 (mainly M41L). These data showing a closeassociation between L210W, T215Y/F, and M41L, and amutual exclusion between K70R and L210W, were con-firmed by analyzing the sequences stored in the HIV-1sequences available through the Stanford HIV RT andProtease Database. Follow-up studies demonstrated thatL210W appeared always after T215Y/F. This observationis consistent with crystallographic studies which sug-gested that the aromatic side chain of Trp 210 could sta-bilize the interaction of Phe/Tyr215 with the dNTP-bind-ing pocket. This molecular cross-talk between aminoacid chains occurs nearby the conserved Asp113 resi-due. Since the lateral chain of Arg70 may also interactwith Asp113, this is likely to create a sterical hindrancearound this residue. Thus, the R->K reversion of codon70 may represent a compensatory mechanism allowinga functional rearrangement of the dNTP-binding pocketin the mutated RT.
- 中文關鍵字: --
- 英文關鍵字: --