Smith R, Klarmann G, Stray K, Vonschwedler U, Schinazi RF, North T, Preston B; Conference on Retroviruses and Opportunistic Infections.
Program Abstr 6th Conf Retrovir Oppor Infect Conf Retrovir Oppor Infect 6th 1999 Chic Ill. 1999 Jan 31-Feb 4; 6th: 91 (abstract no. 126).
University of Utah, Salt Lake City.
We have shown that a P156S mutation in the reverse transcriptase (RT) of feline immunodeficiency virus (FIV) confers resistance to the combination of (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC) and 3'-azido-3'-deoxythymidine (AZT). Here we examine the potential for the corresponding mutation to confer resistance to the combination of AZT+3TC in HIV-1. A molecular clone of NL4-3 containing the P157S mutation in RT was constructed by site-directed mutagenesis. This clone produced wild-type levels of infectious virions in cell culture. Susceptibility to AZT, 3TC, and 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) was determined using a focus reduction assay. P157S conferred 5-fold resistance to 3TC, as compared to the >100-fold resistance of M184V. Both M184V and P157S mutants also displayed a 2-fold hypersensitivity to AZT and PMPA which was consistently reproducible in two or more independent experiments. Studies with purified recombinant M184V and P157S RTs support the phenotypic data with regard to 3TC susceptibility. Thus P157S HIV-1 mutants possess low-level resistance to 3TC, but do not share the AZT+3TC dual-resistance phenotype displayed by P156S mutants of FIV. The P157S mutation has been observed in viral genomes from at least one patient receiving 3TC. Together these data suggest that low-level drug resistant and hypersensitivity alleles may exist in viral populations in vivo.
Publication Types:
Keywords:
- Adenine
- Animals
- Cats
- HIV-1
- Humans
- Immunodeficiency Virus, Feline
- In Vitro
- Lamivudine
- Mutagenesis, Site-Directed
- Mutation
- Phosphonic Acids
- Point Mutation
- RNA-Directed DNA Polymerase
- Zidovudine
- genetics
- tenofovir
Other ID:
UI: 102188757
From Meeting Abstracts