Antiviral Activity in vitro of the INI, Dolutegravir, against Raltegravir-resistant HIV-2 Mutants
Masanori Kobayashi*1, T Seki1, T Yoshinaga1, A Sato1, T Fujiwara1, M Underwood2, and B Johns2
1Shionogi & Co Ltd, Osaka, Japan and 2GlaxoSmithKline, Res Triangle Park, NC, US
Background: Dolutegravir (DTG; S/GSK1349572)’s barrier to resistance has been demonstrated for HIV-1 in vitro (retains activity against single mutations) and in the clinic (no integrase [IN] mutations through 96 weeks in SPRING-1). Herein we demonstrate DTG’s profile against clinically relevant IN mutants of HIV-2.
Methods: We constructed 9 ratelgravir (RAL) resistance-associated site-directed molecular clones from the wild type molecular clone ROD. Viral fitness was assessed with replication in peripheral blood mononuclear cells (PBMC) or with M8166 cells. Mutations assessed were primarily those associated with RAL-resistant viruses observed in clinical trials, and included multiple mutations in the RAL resistance pathways (Y143C/H/R, Q148H/K/R, and N155H, signature as well as secondary mutations). Replication of 3 site-directed molecular clones (Q148K, T97A/Y143C, G140T/Q148R/N155H) could not be observed in PBMC or M8166 cells. The fold changes in susceptibility against the remaining 6 site-directed molecular clones were determined with a cell based assay.
Results: Still sensitive (using cutoff fold-change <5) to DTG were 4 clones—S163D, G140A/Q148R, A153G/N155H/S163G, and E92Q/T97A/N155H/S163D. DTG showed reduced activity against E92Q/N155H (fold-change 8.5) and G140S/Q148R (fold-change 17). RAL and elvitegravir (EVG) showed reduced activity, with 4 and 5 mutant viruses falling into the highly resistant category (fold-changes >10), respectively. S163D was sensitive to all 3 INI. With the exception of S163D, all viral mutants tested had low replication rates compared with wild type virus ROD.
Conclusions: As observed for HIV-1, DTG also has limited cross-resistance to RAL-resistant HIV-2. Unlike RAL and EVG, single mutations and even combinations of mutations were not associated with substantial loss of activity for DTG. These data show the potential for DTG in the treatment of RAL and EVG resistant HIV-2 infections.