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Abstract
Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)–derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.
HIV drugs can dampen inflammation, too
Nucleoside reverse transcriptase inhibitors (NRTIs) stop HIV in its tracks by blocking reverse transcription, a process critical for HIV to replicate its genome. Fowler et al. found that in mice, these drugs also block inflammation caused by a large protein complex called the NLRP3 inflammasome. This activity is independent of the drugs' ability to block reverse transcription. Instead, the drugs block the activity of the ion channel P2X7, which activates the NLRP3 inflammasome. NRTIs improved outcomes in several NLRP3 inflammasome-dependent mouse models of inflammation, including age-related macular degeneration and graft-versus-host disease.
Science, this issue p. 1000
