The contribution of HIV fitness to the evolution pattern of reverse transcriptase inhibitor resistance

Elijah Paintsil, Asa Margolis, Jennifer A. Collins, Louis Alexander

Research output: Contribution to journalArticlepeer-review

Abstract

All currently recommended anti-retroviral therapy protocols employ reverse transcriptase inhibitors (RTIs). However, mutations within the reverse transcriptase (RT) domain can lead to resistance to these agents and treatment failure. The contribution of the fitness of drug-resistant species to the evolution of RTI resistance has not been elucidated despite its potential implications for therapeutic strategies. In this study we utilized a competitive fitness assay to assess the relative fitness of 13 drug-resistant HIV-1 mutants in the presence and absence of inhibitor. Among these mutants were thymidine analog mutations (TAMs) such as 41L/210W/215Y and 67N/70R/219Q, as well as single mutants such as 103N and 181C that confer high-level resistance to non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as nevirapine. These studies revealed that 67N/70R and 67N/70R/219Q were fitter than the 70R progenitor species, and the acquisition of 41L by 215Y substantially increased its fitness in the absence of drug. We also observed that 215Y was more fit than 70R and 67N/70R, and that 41L/215Y and 41L/210W/215Y were the most-fit species in the presence of zidovudine. Moreover, 103N was fitter than 181C without nevirapine but less fit with nevirapine. From these studies we conclude that viral fitness contributes substantially to the evolutionary pattern of TAMs suggesting that, as for protease inhibitor resistance, mutations can act in primary (increasing resistance) and secondary (increasing fitness) capacities. We also surmise that drug resistance and fitness are competing forces underlying the emergence of nevirapine resistant mutants 103N and 181C.

Original languageEnglish (US)
Pages (from-to)425-430
Number of pages6
JournalJournal of Medical Virology
Volume78
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

Keywords

  • Anti-retroviral therapy
  • Drug resistance
  • Viral fitness

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

Fingerprint Dive into the research topics of 'The contribution of HIV fitness to the evolution pattern of reverse transcriptase inhibitor resistance'. Together they form a unique fingerprint.

Cite this