title: In vitro activity of dolutegravir against wild-type and integrase inhibitor-resistant HIV-2.
abstract: BACKGROUND
  Dolutegravir recently became the third integrase strand transfer inhibitor (INSTI) approved for use in HIV-1-infected individuals. In contrast to the extensive dataset for HIV-1, in vitro studies and clinical reports of dolutegravir for HIV-2 are limited. To evaluate the potential role of dolutegravir in HIV-2 treatment, we compared the susceptibilities of wild-type and INSTI-resistant HIV-1 and HIV-2 strains to the drug using single-cycle assays, spreading infections of immortalized T cells, and site-directed mutagenesis.
  
  
  RESULTS
  HIV-2 group A, HIV-2 group B, and HIV-1 isolates from INSTI-naïve individuals were comparably sensitive to dolutegravir in the single-cycle assay (mean EC50 values = 1.9, 2.6, and 1.3 nM, respectively). Integrase substitutions E92Q, Y143C, E92Q + Y143C, and Q148R conferred relatively low levels of resistance to dolutegravir in HIV-2ROD9 (2- to 6-fold), but Q148K, E92Q + N155H, T97A + N155H and G140S + Q148R resulted in moderate resistance (10- to 46-fold), and the combination of T97A + Y143C in HIV-2ROD9 conferred high-level resistance (>5000-fold). In contrast, HIV-1NL4-3 mutants E92Q + N155H, G140S + Q148R, and T97A + Y143C showed 2-fold, 4-fold, and no increase in EC50, respectively, relative to the parental strain. The resistance phenotypes for E92Q + N155H, and G140S + Q148R HIV-2ROD9 were also confirmed in spreading infections of CEM-ss cells.
  
  
  CONCLUSIONS
  Our data support the use of dolutegravir in INSTI-naïve HIV-2 patients but suggest that, relative to HIV-1, a broader array of replacements in HIV-2 integrase may enable cross-resistance between dolutegravir and other INSTI. Clinical studies are needed to evaluate the efficacy of dolutegravir in HIV-2-infected individuals, including patients previously treated with raltegravir or elvitegravir.
authors: Robert A
authors: RA
authors: Smith
authors: Dana N
authors: DN
authors: Raugi
authors: Charlotte
authors: C
authors: Pan
authors: Papa Salif
authors: PS
authors: Sow
authors: Moussa
authors: M
authors: Seydi
authors: James I
authors: JI
authors: Mullins
authors: Geoffrey S
authors: GS
authors: Gottlieb
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
chemical_list: D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir