Mutations in the HIV type 1 integrase of patients receiving long-term dideoxynucleoside therapy do not confer resistance to zidovudine.
Metabolites of AZT can inhibit HIV-1 integrase in vitro (Mazumder A, et al., Proc Natl Acad Sci USA 1994;91:5771-5775). To determine if long-term dideoxynucleoside therapy can lead to the emergence of HIV-1 AZT-resistant variants containing mutations in the integrase, we have sequenced the proviral DNA encoding the HIV-1 integrase of nine HIV-1-infected patients at different time points during treatment. Four of the nine patients developed mutations during the course of treatment. Although most mutations occurred at nonconserved amino acids, one patient developed a mutation at codon (R166T), a residue that is conserved among all integrases from known HIV-1 isolates. This mutation was introduced in the recombinant HIV-1 integrase protein to determine if it could confer resistance to AZT in vitro. We show that the R166T integrase mutant is still proficient at carrying 3'-processing and 3' end-joining but that the enzyme is not resistant to AZT-TP. Our results suggest that it is unlikely that integrase inhibition contributes to the antiviral activity of AZT.
Pilon
A A
AA
Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Marchand
C
C
Kavlick
M F
MF
Bajaj
K
K
Owen
J
J
Mitsuya
H
H
Pommier
Y
Y
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004279:DNA, Viral / Q000032:analysis; D004352:Drug Resistance, Microbial; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011533:Proviruses; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013997:Time Factors; D015215:Zidovudine / Q000494:pharmacology* / Q000627:therapeutic use
D019380:Anti-HIV Agents; D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D019427:HIV Integrase