Novel deletion of HIV type 1 reverse transcriptase residue 69 conferring selective high-level resistance to nevirapine.
A novel deletion of residue 69 of the HIV-1 reverse transcriptase (RT) gene was detected in combination with mutations V75I/V and F77L/F in a patient with partial virological response to several antiretroviral drug regimens, including stavudine (D4T), didanosine (DDI), lamivudine (3TC), saquinavir (SQV), and nevirapine (NVP). Longitudinal analysis of samples revealed that this deletion emerged upon reinitiation DDI/D4T therapy following a toxicity-induced short discontinuation of all antiretrovirals. Analysis of the resistance phenotype showed a greater than 62-fold increase of the IC50 of NVP, but no significant change in sensitivity to other single nonnucleoside reverse transcriptase inhibitors (NNRTIs). The mutated virus showed only a moderately reduced sensitivity to DDI (6.7-fold) and D4T (4.8 fold). In a subsequent sample 3 months later additional RT mutations were found, including A62V, Y188L, and Q151M, conferring high-level cross-resistance to multiple nucleoside analogs. Our findings provide evidence that the deletion of RT residue 69 selectively confers high-level NVP resistance.
Suzuki
K
K
Centre for Immunology, St. Vincent's Hospital, Sydney, NSW 2010, Australia. K.Suzuki@cfi.unsw.edu.au
Kaufmann
G R
GR
Mukaide
M
M
Cunningham
P
P
Harris
C
C
Leas
L
L
Kondo
M
M
Imai
M
M
Pett
S L
SL
Finlayson
R
R
Zaunders
J
J
Kelleher
A
A
Cooper
D A
DA
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008969:Molecular Sequence Data; D019829:Nevirapine / Q000494:pharmacology*; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D012641:Selection, Genetic; D017384:Sequence Deletion / Q000235:genetics*
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase