Paper

P2X antagonists inhibit HIV-1 productive infection and inflammatory cytokines IL-10 and IL-1 in a human tonsil explant model

Lim, Jean K, Gopal, Ramya, Chen, Benjamin K, O'brien, Meagan, Bhardwaj, Nina, Hoffman, Kevin W, Brown, Julia A, Swartz, Talia H, Durham, Natasha, Tweel, Benjamin, Soare, Alexandra Y

2018

Overview

HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated pro-inflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. A human ex vivo human tonsil histo-culture infection model was developed to support HIV-1 productive infection and stimulated inflammatory cytokine interleukin-1 beta (IL-1 ) and immunosuppressive cytokine, interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. The purinergic P2X1 receptor antagonist, NF449, the purinergic P2X7 receptor antagonists, A438079, and azidothymidine (AZT) were tested in HIV-1 infected human tonsil explants to compare inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection but P2X-selective antagonists (NF449, and A438079) significantly lowered HIV-stimulated IL-10 and IL-1 . We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood as compared to lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.

• Publisher: Cold Spring Harbor Laboratory Press
• Subject: Chronic infection / Cytokines / Explants / HIV / Human immunodeficiency virus / Immune system / Immunosuppressive agents / Infections / Inflammation / Interleukin 1 / Interleukin 10 / Lymphoid tissue / Peripheral blood / Purine P2X receptors / Purine receptors / Tonsil / Zidovudine