title: Thiazolides Elicit Anti-Viral Innate Immunity and Reduce HIV Replication.
abstract: Nitazoxanide (Alinia(®), NTZ) and tizoxanide (TIZ), its active circulating metabolite, belong to a class of agents known as thiazolides (TZD) endowed with broad anti-infective activities. TIZ and RM-4848, the active metabolite of RM-5038, were shown to stimulate innate immunity in vitro. Because natural resistance to HIV-1 infection in HIV-exposed seronegative (HESN) individuals is suggested to be associated with strong innate immune responses, we verified whether TIZ and RM-4848 could reduce the in vitro infectiousness of HIV-1. Peripheral blood mononuclear cells (PBMCs) from 20 healthy donors were infected in vitro with HIV-1BaL in the presence/absence of TIZ or RM4848. HIV-1 p24 were measured at different timepoints. The immunomodulatory abilities of TZD were evaluated by the expression of type I IFN pathway genes and the production of cytokines and chemokines. TZD drastically inhibited in vitro HIV-1 replication (>87%). This was associated with the activation of innate immune responses and with the up-regulation of several interferon-stimulated genes (ISGs), including those involved in cholesterol pathway, particularly the cholesterol-25 hydroxylase (CH25H). TZD inhibition of HIV-1 replication in vitro could be due to their ability to stimulate potent and multifaceted antiviral immune responses. These data warrant the exploration of TZD as preventive/therapeutic agent in HIV infection.
authors.affiliation: Department of Biomedical and Clinical Sciences L. Sacco, University of Milano, Italy.
authors.forename: Daria
authors.initials: D
authors.lastname: Trabattoni
authors.affiliation: Department of Biomedical and Clinical Sciences L. Sacco, University of Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gnudi
authors.affiliation: Department of Biomedical and Clinical Sciences L. Sacco, University of Milano, Italy.
authors.forename: Salomè V
authors.initials: SV
authors.lastname: Ibba
authors.affiliation: Department of Biomedical and Clinical Sciences L. Sacco, University of Milano, Italy.
authors.forename: Irma
authors.initials: I
authors.lastname: Saulle
authors.affiliation: Don C Gnocchi Foundation, Milano, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Agostini
authors.affiliation: Department of Biomedical and Clinical Sciences L. Sacco, University of Milano, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Masetti
authors.affiliation: Department of Biomedical and Clinical Sciences L. Sacco, University of Milano, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Biasin
authors.affiliation: Romark Laboratories, L.C., Tampa, Florida, USA.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Rossignol
authors.affiliation: Don C Gnocchi Foundation, Milano, Italy.|Department of Physiopathology and Transplants, University of Milano, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005786:Gene Expression Regulation; D016655:HIV Core Protein p24 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000276:immunology* / Q000821:virology; D013844:Thiazoles / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016655:HIV Core Protein p24; D013844:Thiazoles; C104067:tizoxanide; D003577:Cytochrome P-450 Enzyme System