ArticleMicrobiology spectrum2026
The LEDGIN GS-9822 inhibits HIV-2 infection and enhances HIV-2 latency.
Article in Microbiology spectrum, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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: HIV latent reservoirs are the major hurdle preventing HIV cure. LEDGINs could be used as part of a "block-and-lock" functional cure strategy to induce a state of deep latency in HIV-1 reservoirs and prevent viral rebound in the absence of antiretroviral therapy. Previous generations of LEDGINs were not active against SIV, and therefore, they could not be used to test this strategy in non-human primate (NHP) models. Our study is the first to show the block-and-lock effects of LEDGINs against HIV-2
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