K65R mutation of human immunodeficiency virus type 1 reverse transcriptase encodes cross-resistance to 9-(2-phosphonylmethoxyethyl)adenine

Antimicrob Agents Chemother. 1995 Aug;39(8):1888-91. doi: 10.1128/aac.39.8.1888.

Abstract

Cloned variants of human immunodeficiency virus type 1 that contain the K65R mutation in reverse transcriptase have previously been shown to display approximately 10- to 30-fold resistance against 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and 2',3'-dideoxy-3'-thiacytidine. On the basis of tissue culture studies with both primary T cells and established cell lines, we now report that the K65R mutation confers approximately 12- to 15-fold resistance to 9-(2-phosphonylmethoxyethyl)adenine (PMEA). Likewise, a chain termination system revealed that mutated recombinant K65R reverse transcriptase displays resistance to PMEA diphosphate, the active metabolite of PMEA, in cell-free enzyme assays. Parallel studies have shown that the M184V mutation in reverse transcriptase, associated with high-level resistance against the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine, does not confer resistance to PMEA in tissue culture. Viruses and enzymes that included both the K65R and M184V mutations were resistant to PMEA and PMEa diphosphate, respectively, but only to the extent conferred by the K65R mutation alone.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives*
  • Adenine / pharmacology
  • Antiviral Agents / pharmacology*
  • Cell-Free System
  • Cloning, Molecular
  • Culture Techniques
  • Drug Resistance, Microbial / genetics
  • HIV Infections / microbiology
  • HIV Reverse Transcriptase
  • HIV-1 / enzymology*
  • HIV-1 / genetics*
  • Humans
  • Organophosphonates*
  • RNA-Directed DNA Polymerase / genetics*
  • RNA-Directed DNA Polymerase / metabolism

Substances

  • Antiviral Agents
  • Organophosphonates
  • adefovir
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase
  • Adenine