PT  - JOURNAL ARTICLE
AU  - Alexandra Y. Soare
AU  - Natasha D. Durham
AU  - Ramya Gopal
AU  - Benjamin Tweel
AU  - Kevin W. Hoffman
AU  - Julia A. Brown
AU  - Megan O’Brien
AU  - Nina Bhardwaj
AU  - Jean K. Lim
AU  - Benjamin K. Chen
AU  - Talia H. Swartz
TI  - P2X antagonists inhibit HIV-1 productive infection and inflammatory cytokines IL-10 and IL-1β in a human tonsil explant model
AID  - 10.1101/366179
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 366179
4099  - http://biorxiv.org/content/early/2018/07/10/366179.short
4100  - http://biorxiv.org/content/early/2018/07/10/366179.full
AB  - 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-1β) 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-1β. 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.Importance Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here we describe a class of drugs that target the P2X pro-inflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to both block HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.