NNRTI-selected mutations at codon 190 of human immunodeficiency virus type 1 reverse transcriptase decrease susceptibility to stavudine and zidovudine

Stefania Paolucci, Fausto Baldanti, Giulia Campanini, Reynel Cancio, Amalia Belfiore, Giovanni Maga, Giuseppe Gerna

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)99-103
Number of pages5
JournalAntiviral Research
Volume76
Issue number2
DOIs
Publication statusPublished - Nov 2007

Keywords

  • Drug resistance
  • HIV-1
  • NNRTI
  • NRTI
  • RT mutations

ASJC Scopus subject areas

  • Virology
  • Pharmacology

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