title: 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 of compensatory mutations in combination with higher fidelity NRTI resistance mutations and the subsequent reversion of NRTI-resistant mutations upon cessation of antiretroviral treatment lend support to the notion that higher fidelity exacts a fitness cost. Potential mechanisms for reduced viral fitness are a smaller pool of mutant strains available to respond to immune or drug pressure, slower rates of replication, and a limitation to the dNTP tropism of the virus. Unraveling the relationship between replication fidelity and fitness should lead to a greater understanding of the evolution and control of HIV.
authors.affiliation: Department of Microbiology and Immunology, The University of Melbourne , Parkville, VIC, Australia .
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Lloyd
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kent
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Winnall
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D014644:Genetic Variation; D015658:HIV Infections / Q000188:drug therapy / Q000235:genetics / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics* / Q000254:growth & development; D006801:Humans; D059645:Mutation Rate; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D014779:Virus Replication / Q000235:genetics*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase