Rare one and two amino acid inserts adjacent to codon 103 of the HIV-1 reverse transcriptase (RT) affect susceptibility to non-nucleoside RT inhibitors.
HIV-1 strains that possess a one or two amino acid insert between codons 102 and 103 of the reverse transcriptase (RT) gene were identified in three HIV-1-infected individuals. Each strain also had one or more known mutations associated with nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs). Recombinant viruses from these strains had reduced susceptibility to efavirenz and nevirapine, and homology modelling predicted a loss of binding contacts with efavirenz. Mutagenesis studies indicated that replication of insert-containing strains was dependent on RT gene mutations and polymorphisms that co-evolved with the insert. These results suggest that inserts in the NNRTI-binding pocket contribute to NNRTI resistance, but are tolerated only under specific genetic conditions.
Winters
Mark A
MA
Center for AIDS Research, Stanford University, Stanford, CA, USA. mark.winters@stanford.edu
Kagan
Ron M
RM
Kovari
Ladislau
L
Heseltine
Peter N R
PN
Merigan
Thomas C
TC
D000480:Alkynes; D048588:Benzoxazines; D002460:Cell Line; D003062:Codon; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D019829:Nevirapine / Q000494:pharmacology; D009705:Nucleosides; D010078:Oxazines / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000737:chemistry / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
D000480:Alkynes; D048588:Benzoxazines; D003062:Codon; D003521:Cyclopropanes; D009705:Nucleosides; D010078:Oxazines; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D012194:RNA-Directed DNA Polymerase; C098320:efavirenz