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In Vitro Directed Evolution of a Restriction Endonuclease with More Stringent Specificity
Published on: March 25, 2020
Basis for early and preferential selection of the E138K mutation in HIV-1 reverse transcriptase
Matthew McCallum1, Maureen Oliveira, Ruxandra-Ilinca Ibanescu
1McGill University AIDS Centre, Lady Davis Institute of Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
Antimicrobial Agents and Chemotherapy
|July 17, 2013
Summary
HIV-1 reverse transcriptase (RT) shows a mutational bias, favoring G→A changes like E138K, which impacts drug resistance evolution. This bias is observed both in selection experiments and in drug-naive patients.
Area of Science:
- Virology
- Molecular Biology
- Genetics
Background:
- Etravirine (ETR) and rilpivirine preferentially select for the E138K mutation in HIV-1 reverse transcriptase (RT).
- The E138K mutation, a G→A change, is observed despite other substitutions at position E138 conferring greater drug resistance.
Purpose of the Study:
- To investigate the hypothesized mutational bias for the E138K substitution in HIV-1 RT.
- To monitor the emergence of various E138 substitutions during ETR selection and in drug-naive patients.
Main Methods:
- Developed allele-specific PCR to track E138A/G/K/Q/R/V emergence during ETR selection.
- Conducted competition experiments with mutated viruses.
- Quantified E138 minority species prevalence in drug-naive patients using ultradeep sequencing (UDS).
Main Results:
- E138K and E138G consistently emerged first during ETR selection, followed by E138A and E138Q; E138R was not selected.
- E138K was found as a minority species in 23% of drug-naive subtype B patients, confirmed by UDS.
- UDS revealed other minority species, consistent with HIV RT mutational bias, with no evidence of APOBEC3-hypermutation.
Conclusions:
- Confirms a significant mutational bias in HIV-1, particularly G→A mutations.
- Highlights the crucial role of this bias in the evolution of HIV-1 drug resistance.
- Suggests E138K's prevalence may be influenced by factors beyond simple fitness cost.
