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 di deoxynucleoside therapy can lead to the emergence of HIV-1 AZT-resistant va riants containing mutations in the integrase, we have sequenced the provira l DNA encoding the HIV-1 integrase of nine HIV-1-infected patients at diffe rent time points during treatment. Four of the nine patients developed muta tions during the course of treatment. Although most mutations occurred at n onconserved 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 t o 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 s uggest that it is unlikely that integrase inhibition contributes to the ant iviral activity of AZT.