title: NNRTI-selected mutations at codon 190 of human immunodeficiency virus type 1 reverse transcriptase decrease susceptibility to stavudine and zidovudine.
abstract: The non-nucleoside reverse transcriptase (RT) inhibitor (NNRTI)-binding pocket of HIV-1 RT spans codons 100-110, 180-190 and 220-240 and mutations in these domains are responsible for HIV-1 NNRTI resistance. Recombinant HIV-1 strains carrying G190S/A/E, G190S+T215Y, T215Y and K103N mutations were constructed to evaluate susceptibility to both NNRTIs and nucleoside RT inhibitors (NRTIs). In addition, purified recombinant RT enzymes were obtained to determine the degree of in vitro inhibition by drugs of both classes. High-level resistance to nevirapine and moderate level resistance to both stavudine and zidovudine were associated with G190S/A/E substitutions. The simultaneous presence of G190S and T215Y decreased stavudine and zidovudine susceptibility more than T215Y alone. On the other hand, G190S was associated with a marked decrease in RT catalytic efficiency, while T215Y showed a more limited effect. Interestingly, the simultaneous presence of G190S and T215Y was associated with a reduction in the impairment of the G190S-mutated enzyme. Mutations in the HIV-1 RT NNRTI binding pocket may be associated with cross-resistance to NRTI. Selection of double mutants, with further decrease in NRTI susceptibility, might be favoured by the compensatory effect of T215Y on the reduction of RT catalytic efficiency associated with G190S.
authors.affiliation: Servizio di Virologia, IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Paolucci
authors.forename: Fausto
authors.initials: F
authors.lastname: Baldanti
authors.forename: Giulia
authors.initials: G
authors.lastname: Campanini
authors.forename: Reynel
authors.initials: R
authors.lastname: Cancio
authors.forename: Amalia
authors.initials: A
authors.lastname: Belfiore
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gerna
mesh_terms: D019943:Amino Acid Substitution; D019380:Anti-HIV Agents / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics*; D054303:HIV Reverse Transcriptase / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D009154:Mutation; D019829:Nevirapine / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018119:Stavudine / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019829:Nevirapine; D018119:Stavudine; D054303:HIV Reverse Transcriptase