Resistance to template-analogue inhibitors linked to impaired replication
HIV strains that develop resistance to template-analogue reverse transcriptase inhibitors (TRTIs) also develop crippling defects, according to researchers in New York.
Dr Timothy S Fisher and colleagues at the Albert Einstein College of Medicine in Bronx, New York, studied the effects of TRTI resistance mutations on viral fitness.
Mutations that confer high-level TRTI resistance significantly impaired HIV replication, the researchers found.
They exposed wild-type viruses to RT1t49, a DNA aptamer that binds to the template-primer cleft of HIV reverse transcriptase. Strains with one copy of the resulting mutations (N255D or N265D) developed mild TRTI resistance, while the presence of both polymorphisms was associated with high-level resistance, according to the report.
However, these mutations also interfered with the interaction between reverse transcriptase and the template-primer. As a result, TRTI-resistant strains were unable to replicate effectively, study data showed.
Although TRTI resistance mutations do not necessarily impair reverse transcriptase activity, the overlap between binding pockets for therapeutic aptamers and the template-primer helps select for mutations that do.
“Potent inhibition and a built-in mechanism to render aptamer-resistant viruses replication defective make this an attractive class of inhibitors,” Fisher and colleagues concluded.
Source: Michael Greer, for AIDSWEEKLY
Fisher TS, Joshi P, Prasad VR. Mutations that confer resistance to template-analog inhibitors of human immunodeficiency virus (HIV) type 1 reverse transcriptase lead to severe defects in HIV replication. J Virol 2002 Apr;76(8):4068-72