The HIV-1 reverse transcriptase A62V mutation influences replication fidelity and viral fitness in the context of multi-drug-resistant mutations

José O. Maldonado, Louis M. Mansky

Research output: Contribution to journalArticlepeer-review

Abstract

Emergence of human immunodeficiency virus type 1 (HIV-1) drug resistance arises from mutation fixation in the viral genome during antiretroviral therapy. Primary mutations directly confer antiviral drug resistance, while secondary mutations arise that do not confer drug resistance. The A62V amino acid substitution in HIV-1 reverse transcriptase (RT) was observed to be associated with multi-drug resistance, but is not known to be a resistance-conferring mutation. In particular, A62V was observed in various multi-dideoxynucleoside resistant (MDR) mutation complexes, including the Q151M complex (i.e., A62V, V75I, F77L, F116Y, and Q151M), and the T69SSS insertion complex, which has a serine–serine insertion between amino acid positions 69 and 70 (i.e., M41L, A62V, T69SSS, K70R, and T215Y). However, what selective advantage is conferred to the virus remains unresolved. In this study, we hypothesized that A62V could influence replication fidelity and viral fitness with viruses harboring the Q151M and T69SSS MDR mutation complexes. A single-cycle replication assay and a dual-competition fitness assay were used to assess viral mutant frequency and viral fitness, respectively. A62V was found to increase the observed lower mutant frequency identified with each of the viruses harboring the MDR mutation complexes in the single-cycle assay. Furthermore, A62V was observed to improve viral fitness of replication-competent MDR viruses. Taken together, these observations indicate an adaptive role of A62V in virus replication fidelity and viral fitness, which would likely enhance virus persistence during drug-selective pressure.

Original languageEnglish (US)
Article number376
JournalViruses
Volume10
Issue number7
DOIs
StatePublished - Jul 18 2018

Bibliographical note

Funding Information:
Funding: This work was supported by NIH grants R01 GM105876 and R01 GM124279. JOM was supported by NIH grants F30 DE22286 and T32 AI083196 (Institute for Molecular Virology Training Program).

Funding Information:
This work was supported by NIH grants R01 GM105876 and R01 GM124279. JOM was supported by NIH grants F30 DE22286 and T32 AI083196 (Institute for Molecular Virology Training Program). We thank Eric Arts (Western University) for reagents and Michael Dapp for technical assistance.

Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Compensatory mutation
  • Immunodeficiency virus
  • Lentivirus
  • Viral fitness
  • Viral mutagenesis

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