P2X1 Selective Antagonists Block HIV-1 Infection through Inhibition of Envelope Conformation-Dependent Fusion—Soare 2020
Purinergic receptors regulate inflammation by detecting extracellular nucleotides released by dying or infected cells. Inhibiting these inflammatory receptors prevents HIV-1 productive infection and inflammation. Receptor type and interaction mechanism are unknown. NF279 and NF449 block P2X1 receptors in cell lines, primary cells, and HIV-1 envelope (Env) clades. NF279 and NF449 inhibited viral membrane fusion and productive infection in HIV-1 Env isolates. A mutant virus with a truncation deletion of the C-terminal tail of HIV-1 Env glycoprotein 41 (gp41) was less sensitive to P2X1 antagonists, suggesting that Env shape may influence inhibition by these molecules. P2X7 antagonist A438079 showed no effect on productive infection and fusion. NF279 and NF449 prevented the broadly neutralizing antibody PG9 from blocking productive infection, suggesting that these medicines may disrupt viral membrane fusion by antagonizing HIV-1 Env at gp120 V1V2. P2X1 antagonism inhibits HIV-1 membrane fusion via Env, according to our findings. These chemicals impede HIV-1 fusion, and future investigations will produce small molecules to limit HIV-1 entry by this method. IMPORTANCE HIV-1 patients have increased rates of chronic inflammation-related non-communicable comorbidities despite successful therapy. Emerging data suggests P2X1 receptors mediate chronic inflammation, although the mechanism is uncertain. P2X1 receptor antagonism reduces HIV-1 infection. HIV-1 Env interference inhibits multiple viral clades. These findings indicate P2X1 antagonists as new treatments that potentially block many viral clades and reduce inflammation.
Soare, A. Y., Malik, H. S., Durham, N. D., Freeman, T. L., Alvarez, R., Patel, F., Satija, N., Upadhyay, C., Hioe, C. E., Chen, B. K., & Swartz, T. H. (2020). P2X1 Selective Antagonists Block HIV-1 Infection through Inhibition of Envelope Conformation-Dependent Fusion. Journal of virology, 94(6), e01622-19. https://doi.org/10.1128/JVI.01622-19
