The R263K substitution in HIV-1 subtype C is more deleterious for integrase enzymatic function and viral replication than in subtype B

Thibault Mesplede, Peter K. Quashie, Said Hassounah, Nathan Osman, Yingshan Han, Jiaming Liang, Diane N. Singhroy, Mark A. Wainberg

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Objectives: Dolutegravir is an integrase strand-transfer inhibitor that has shown unprecedented robustness against the emergence of HIV drug-resistant strains in treatment-naive individuals. The R263K substitution in integrase was identified through culture selection as a resistance-associated substitution for dolutegravir and was recently detected in two treatment-experienced participants in the SAILING clinical trial, who experienced dolutegravir-based treatment failure, one of whom was infected by a subtype C virus. The objective of this study was to characterize the R263K substitution in HIV-1 subtype C integrase. Design and methods: We used cell-free strand transfer assays and tissue culture experiments to characterize the R263K substitution in HIV-1 subtype C integrase in comparison with subtype B. Results: Cell-free biochemical assays showed that the R263K substitution diminished subtype C integrase strand-transfer activity by decreasing the affinity of integrase for target DNA. Similarly, both viral infectiousness and replication capacity were reduced by the R263K substitution in tissue culture. Decrease in enzyme activity and viral infectiousness exceeded 35 and 50%, respectively - significantly more than in HIV-1 subtype B. R263K in HIV-1 subtype C also conferred low levels of resistance against dolutegravir and high levels of cross-resistance against elvitegravir, but not raltegravir. Conclusions: The R263K substitution is more deleterious to integrase strand-transfer activity and viral infectiousness in HIV-1 subtype C than in subtype B. Our results suggest that cross-resistance may prevent treatment-experienced individuals who are experiencing treatment failure with dolutegravir from being subsequently treated with elvitegravir.

Original languageEnglish
Pages (from-to)1459-1466
Number of pages8
JournalAIDS
Volume29
Issue number12
DOIs
Publication statusPublished - 31 Jul 2015
Externally publishedYes

Keywords

  • Dolutegravir
  • Drug resistance
  • HIV
  • HIV-1 subtype C
  • Integrase
  • R263K

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