In vitro selection and characterization of human immunodeficiency virus type 1 resistant to Zidovudine and tenofovir

In this study, we undertook to generate HIV-1 resistance to PMPA by in vitro passage and to characterize the cross-resistance patterns and RT mutations in the generated resistant virus. The HIV-1 A102-resistant to AZT was serially passaged for 4 months in the presence of increasing concentrations of PMPA up to maximum of 40 microM on the fresh MT-2 cells. After 25 passages, HIV-1 developed decreased sensitivity to PMPA after long-term in vitro exposure. Selected HIV-1 mutants were characterized by decreased susceptibility to PMPA (4-fold). This decrease could be related to PMPA resistant caused by an amino acid change associated with a V148M substitution. From these results, additional studies will be needed to determine whether a similar mutation in HIV RT develops in patients receiving PMPA or its orally bioavailable prodrug, tenofovir dipivoxil fumarate.