FIG 7.

Model for signaling in HIV-1-mediated inflammation. (A) Table summarizing observations from drug activity across PBMC and tonsil models. Arrows indicate relative magnitudes of the effects of inhibition in each of the models depicted. (B) NF449 inhibits HIV-1 productive infection and downstream signaling of the NLRP3 inflammasome. This pathway is activated in concert with TLR4 receptor activation, which can drive caspase-1 to cleave pro-IL-1β to mature IL-1β. Mature IL-1β can be secreted or induce pyroptosis in CD4⁺ T cells. This signaling can also activate NF-κB-dependent transcriptional regulation of IL-10. Inhibition of this mechanism by NF449 may explain enhanced cell survival in tonsil cells. A438079, in contrast, may act directly on P2X7 to inhibit receptor signaling that is required for HIV-1 entry. P2X7 inhibition results in the inability to activate the NLRP3 inflammasome and pyroptosis in tonsil cells, which does not occur in PBMCs. Therefore, A438079 depends on intact inflammasome signaling to exert inhibition on HIV-1 productive infection. (Printed with permission from Mount Sinai Health System.)