The LEDGIN GS-9822 inhibits HIV-2 infection and enhances HIV-2 latency

HIV integration is targeted toward active transcription units through the interaction of HIV integrase with the cellular co-factor LEDGF/p75. LEDGINs, small molecule inhibitors of this interaction, reduce HIV-1 integration and retarget residual proviruses away from active transcription units, resulting in a more latent phenotype. LEDGF/p75 interacts with all lentiviral integrases, but early-generation LEDGINs are not effective against HIV-2 or SIV, as they carry a methionine instead of an alanine at the LEDGIN interaction spot. The LEDGIN GS-9822 (Gilead Sciences) was optimized for activity against the HIV-1 integrase A128T LEDGIN resistance mutation, which we hypothesized could confer activity against HIV-2 and SIV. Using AlphaScreen, we show that GS-9822 blocks the interaction of HIV-2 and SIV integrase with LEDGF/p75. In cell culture, we show preliminary data that GS-9822 achieves nanomolar activity against HIV-2 and SIV replication. Using HIV-2 OGH, a single round double reporter construct that can distinguish between latently and productively transduced cells, we show that GS-9822 inhibits integration and that residual HIV-2 integrants are more latent and refractory to reactivation. Finally, using next-generation sequencing, we showed that GS-9822 retargets HIV-2 integration away from active transcription units and toward a more repressive epigenetic chromatin environment. We demonstrate for the first time that LEDGINs can inhibit HIV-2 integration and replication. As GS-9822 shows a difficult-to-monitor urothelial toxicity in non-human primates, future research with new LEDGIN congeners should look into the effects of LEDGINs on HIV-2 and SIV, as this could pave the way for non-human primate studies on the "block and lock" effect of LEDGINs. IMPORTANCE: and shows the preliminary data of activity against SIV as well. Although GS-9822 itself cannot be used in NHP models, due to urothelial toxicity, this means it is possible to design new LEDGINs with SIV activity for future experiments with the "block-and-lock" strategy in non-human primate models. In addition, we show that LEDGINs can achieve their latency-promoting effects against HIV-2 as well.