Mechanistic Studies to Understand the Progressive Development of Resistance in Human Immunodeficiency Virus Type 1 Reverse Transcriptase to Abacavir

摘要: Abacavir has been shown to select for multiple resistant mutations in the human immunodeficiency type 1 (HIV-1) pol gene. In an attempt understand molecular mechanism of resistance response abacavir, and nucleoside analogs general, a set reverse transcriptase mutants were studied evaluate their kinetics nucleotide incorporation removal. It was found that, similar multidrug-resistant mutant (RT)Q151M, L74V, M184V, triple containing L74V/Y115F/M184V all caused increased selectivity dGTP over active metabolite abacavir (carbovir triphosphate). However, magnitude observed cell culture previous studies less than that other compounds. Our mechanistic suggest this may be due carbovir triphosphate decreasing overall effect on its efficiency by forming strong hydrophobic interactions RT site. Unlike RTAZTR, no increase rate ATP- or PPi-mediated chain terminator removal relative RTWT could detected any mutants. marked decreases steady-state serve as chain-terminating monophosphate increasing time spent at primer terminus some studied. The showed advantage RTM184V severely impaired ability remove terminator, giving kinetic basis cellular system. Biochemical properties including percentage sites, fidelity, processivity mutant's is perhaps fitness advantage, although further are needed verify hypothesis. These data understanding how confer analogs.