Genotypic, phenotypic, and modeling studies of a deletion in the beta3-beta4 region of the human immunodeficiency virus type 1 reverse transcriptase gene that is associated with resistance to nucleoside reverse transcriptase inhibitors.
Point mutations and inserts in the beta3-beta4 region of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) are associated with resistance to nucleoside analog inhibitors. This report describes HIV-1 strains from seven patients that were found to have a 3-bp deletion in the beta3-beta4 region of the RT gene. These patient strains also had a mean of 6.2 drug resistance-associated mutations in their RT genes (range, 3 to 10 mutations). The deletion was most frequently found in strains with the Q151M mutation. Nonnucleoside RT inhibitor mutations were found in six of seven strains. Culture-based drug sensitivity assays showed that deletion-containing isolates had reduced susceptibility to four to eight RT inhibitors. Site-directed mutagenesis experiments showed that the deletion alone conferred reduced susceptibility to nucleoside analogs. Changes in the three-dimensional models of the RT deletion mutants were consistently observed at the beta3-beta4 loop and at helices C and E in both the presence and the absence of dTTP. Loss of hydrogen bonds between the RT and dTTP were also observed in the RT deletion mutant. These results suggest that the deletion in the RT gene contributes to resistance to several nucleoside analogs through a complex interaction with other mutations in the RT gene.
Winters
M A
MA
Stanford University, Stanford, California 94305, USA. mark.winters@stanford.edu
Coolley
K L
KL
Cheng
P
P
Girard
Y A
YA
Hamdan
H
H
Kovari
L C
LC
Merigan
T C
TC
D004352:Drug Resistance, Microbial; D005838:Genotype; D015658:HIV Infections / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D010641:Phenotype; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016415:Sequence Alignment; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase