title: A selective defect of IFN-gamma- but not of IFN-alpha-induced JAK/STAT pathway in a subset of U937 clones prevents the antiretroviral effect of IFN-gamma against HIV-1.
abstract: IFN-gamma induces transcription of several IFN-stimulated genes (ISGs). Recently, the IFN-gamma-dependent Janus kinase (JAK)/STAT pathway has been shown to mediate the activation of some ISGs, by the sequential phosphorylation of two JAK kinases (JAK1 and JAK2) and of STAT1. Given that the JAK/STAT is the major, but not the only pathway linked to the IFN-gammaR, aim of our work was to investigate the signal-transduction pathway(s) by which IFN-gamma exerts its effects on acute replication of HIV in monocytic cells. To this end, we utilized clones previously derived from the U937 promonocytic cell line, differing for their efficient (plus clones) or inefficient (minus clones) abilities of supporting HIV replication. Unlike IFN-alpha, IFN-gamma did not inhibit HIV replication in plus clones, whereas virus production in minus cells was efficiently inhibited by both types of IFN. Plus clones generated a JAK/STAT signal-transduction pathway in response to IFN-alpha, but not IFN-gamma. In contrast, minus clones responded to either cytokines. The functional defect of plus clones in response to IFN-gamma was correlated to a selective defect of IFN-gammaR2, but not IFN-gammaR1, membrane expression. Surprisingly enough, IFN-gamma stimulation of plus clones induced IFN-stimulated gene factor 3 (ISGF3gamma). These results strongly support the hypothesis that the JAK/STAT pathway is responsible for the antiretroviral effect of IFN-gamma, and further provide evidence for a potential second pathway triggered by IFN-gamma in the absence of IFN-gammaR2 chain cell surface expression and involving ISGF3gamma.
authors.affiliation: AIDS Immunophatogenesis Unit, San Raffaele Scientific Institute, Milan, Italy. bovolenta.chiara@hsr.it
authors.forename: C
authors.initials: C
authors.lastname: Bovolenta
authors.forename: A L
authors.initials: AL
authors.lastname: Lorini
authors.forename: B
authors.initials: B
authors.lastname: Mantelli
authors.forename: L
authors.initials: L
authors.lastname: Camorali
authors.forename: F
authors.initials: F
authors.lastname: Novelli
authors.forename: P
authors.initials: P
authors.lastname: Biswas
authors.forename: G
authors.initials: G
authors.lastname: Poli
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D002999:Clone Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism; D004789:Enzyme Activation / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007113:Immunity, Innate; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000096:biosynthesis; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000502:physiology*; D020298:U937 Cells; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology; D000096743:Interferon gamma Receptor
chemical_list: D019380:Anti-HIV Agents; D004268:DNA-Binding Proteins; D015395:Histocompatibility Antigens Class I; D050856:Interferon Regulatory Factor-1; D050832:Interferon-Stimulated Gene Factor 3; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D016898:Interferon-alpha; D007371:Interferon-gamma; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000096743:Interferon gamma Receptor; C494257:IRF1 protein, human; C494227:IRF9 protein, human; C494079:STAT1 protein, human