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New raltegravir resistance pathways induce broad cross-resistance to all currently used integrase inhibitors

Isabelle Malet1, Laura Gimferrer Arriaga2, Anna Artese3

  • 1Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013, Paris, France INSERM, UMR_S 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, F-75013, Paris, France AP-HP, Laboratoire de Virologie, Hôpital Pité-Salpêtrière, F-75013, Paris, France isabelle.malet@psl.aphp.fr.

The Journal of Antimicrobial Chemotherapy
|April 9, 2014
PubMed
Abstract

Insights

Atypical integrase mutations G118R and F121Y in HIV-1 confer broad cross-resistance to raltegravir, elvitegravir, and dolutegravir. These mutations significantly reduce drug binding and efficacy, impacting treatment options for treatment-experienced patients.

Area of Science:

  • Virology
  • Drug Resistance
  • Molecular Biology

Background:

  • Integrase strand transfer inhibitors (INSTIs) are crucial in HIV-1 therapy.
  • Common INSTI resistance mutations include Y143, Q148, and N155.
  • Atypical mutations like G118R and F121Y are less understood but clinically relevant.

Purpose of the Study:

  • To evaluate the in vitro activity of dolutegravir, raltegravir, and elvitegravir against HIV-1 integrase with atypical G118R and F121Y mutations.
  • To compare the efficacy of these integrase inhibitors against these specific resistance profiles.

Main Methods:

  • Phenotypic susceptibility testing of G118R and F121Y integrase variants against dolutegravir, raltegravir, and elvitegravir.
  • In silico analysis including binding affinity and hydrogen bond network evaluation.

Main Results:

  • G118R and F121Y mutations conferred high-level resistance (fold change >100) to all tested integrase inhibitors.
  • In silico analysis revealed reduced binding affinities and fewer hydrogen bonds for these mutant integrases compared to wild-type.
  • Resistance was observed both with clinically derived integrases and when mutations were tested alone.

Conclusions:

  • The G118R and F121Y mutations induce broad cross-resistance to currently available integrase inhibitors.
  • These findings highlight the importance of considering atypical resistance profiles in HIV-1 treatment failure.
  • Decreased stability of inhibitor-integrase complexes contributes to the observed resistance.
Keywords:
binding affinitydolutegravirelvitegravirphenotyperaltegravir

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