The High Cost of Fidelity

Abstract

The notoriously low fidelity of HIV-1 replication is largely responsible for the virus's rapid mutation rate, facilitating escape from immune or drug control. The error-prone activity of the viral reverse transcriptase (RT) is predicted to be the most influential mechanism for generating mutations. The low fidelity of RT has been successfully exploited by nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs) that halt viral replication upon incorporation. Consequently, drug-resistant strains have arisen in which the viral RT has an increased fidelity of replication, thus reducing analogue incorporation. Higher fidelity, however, impacts on viral fitness. The appearance ..