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A novel genetic pathway of human immunodeficiency virus type 1
resistance to stavudine mediated by the K65R mutation.
Journal of Virology 2003;77 (10):5685-5693.
García-Lerma JG, MacInnes H, Bennett D, Reid P, Nidtha S, Weinstock
H, Kaplan J, Heneine W.
Abstract
Stavudine (d4T) and zidovudine (AZT) are thymidine analogs widely used in the
treatment of human immunodeficiency virus type 1 (HIV-1)-infected persons.
Resistance to d4T is not fully understood, although the selection of AZT
resistance mutations in patients treated with d4T suggests that both drugs
have similar pathways of resistance. Through the analysis of genotypic changes
in nine recombinant viruses cultured with d4T, we identified a new pathway
for d4T resistance mediated by K65R, a mutation not selected by AZT. Passaged
viruses were derived from treatment-naive persons or HIV-1(HXB2) and had
wild-type reverse transcriptase (RT) or T215C/D mutations. K65R was selected
in seven viruses and was associated with a high level of enzymatic resistance
to d4T-triphosphate (median, 16-fold; range, 5- to 48-fold). The role of
K65R in d4T resistance was confirmed in site-directed mutants generated in
three different RT backgrounds. Phenotypic assays based on recombinant single-cycle
replication or a whole-virus multiple replication cycle were unable to detect
d4T resistance in d4T-selected mutants with K65R but detected cross-resistance
to other nucleoside RT inhibitors. Four of the six viruses that had 215C/D
mutations at baseline acquired the 215Y mutation alone or in association
with K65R. Mutants having K65R and T215Y replicated less efficiently than
viruses that had T215Y only, suggesting that selection of T215Y in patients
treated with d4T may be favored. Our results demonstrate that K65R plays
a role in d4T resistance and indicate that resistance pathways for d4T and
AZT may not be identical. Biochemical analysis and improved replication assays
are both required for a full phenotypic characterization of resistance to
d4T. These findings highlight the complexity of the genetic pathways of d4T
resistance and its phenotypic expression.