Thiazolides elicit anti-viral innate immunity and drastically reduce HIV replication in vitro

Background: Nitazoxanide (Alinia®, NTZ) and tizoxanide (TIZ), its active circulating metabolite, belong to a new class of agents known as thiazolides (TZD) that are endowed with a broad anti-infective activity. TIZ and RM-4848, the active circulating metabolite of the new generation thiazolide RM-5038, were also recently shown to potently stimulate innate immunity in vitro. Because natural resistance to HIV-1 infection in HIV-exposed seronegative (HESN) individuals is associated with strong innate immune responses, we verified whether TIZ and RM4848 could reduce in vitro susceptibility to HIV-1. Methods: Peripheral blood mononuclear cells (PBMCs) from 20 healthy donors were infected in vitro with HIV-1BaL in the presence/absence of TIZ or RM-4848. HIV-1 p24 was measured 7 and 10 days post infection. The immunomodulatory abilities of TZD and RM-4848 were evaluated by examining the expression of genes that are part of the type I IFN pathway and are stimulated by IFN (ISGs), as well as the downstream production of cytokines and chemokines. Results: TIZ and RM-4848 drastically (>87%) and consistently inhibited in vitro HIV-1 replication. This was associated with the activation of innate immune responses and with the up-regulation of several ISGs, including those involved in cholesterol metabolism and efflux and in particular cholesterol-25 hydroxylase (CH25H). Conclusions: Thiazolides inhibit HIV-1 replication in vitro possibly as a result of their ability to stimulate potent and multifaceted antiviral immune responses. These data warrant the exploration of thiazolides as preventive/therapeutic agent in HIV infection.