USP18 is a significant driver of memory CD4 T-cell reduced viability caused by type I IFN signaling during primary HIV-1 infection

Autoři: Xavier Dagenais-Lussier aff001;  Hamza Loucif aff001;  Hugo Cadorel aff001;  Juliette Blumberger aff001;  Stéphane Isnard aff002;  Mariana Gé Bego aff003;  Éric A. Cohen aff003;  Jean-Pierre Routy aff002;  Julien van Grevenynghe aff001
Působiště autorů: Institut national de la recherche scientifique (INRS)-Institut Armand-Frappier, 531 boulevard des Prairies, Laval, QC, Canada aff001;  Chronic Viral Illness Service and Division of Hematology, McGill University Health Centre, Glen site, Montréal, Québec, Canada aff002;  Institut de recherches cliniques de Montréal (IRCM), Montréal, QC, Canada aff003;  Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, QC, Canada aff004
Vyšlo v časopise: USP18 is a significant driver of memory CD4 T-cell reduced viability caused by type I IFN signaling during primary HIV-1 infection. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1008060
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008060


The loss of Memory CD4 T-cells (Mem) is a major hallmark of HIV-1 immuno-pathogenesis and occurs early during the first months of primary infection. A lot of effort has been put into understanding the molecular mechanisms behind this loss, yet they still have not been fully identified. In this study, we unveil the unreported role of USP18 in the deleterious effects of sustained type I IFN signaling on Mem, including HIV-1-specific CD4 T-cells. We find that interfering with IFN-I signaling pathway in infected patients, notably by targeting the interferon-stimulated gene USP18, resulted in reduced PTEN expression similar to those observed in uninfected control donors. We show that AKT activation in response to cytokine treatment, T-cell receptor (TcR) triggering, as well as HIV-1 Gag stimulation was significantly improved in infected patients when PTEN or USP18 were inhibited. Finally, our data demonstrate that higher USP18 in Mem from infected patients prevent proper cell survival and long-lasting maintenance in an AKT-dependent manner. Altogether, we establish a direct role for type I IFN/USP18 signaling in the maintenance of total and virus-specific Mem and provide a new mechanism for the reduced survival of these populations during primary HIV-1 infection.

Klíčová slova:

Apoptosis – Cytokines – Flow cytometry – Genetic interference – HIV-1 – Memory T cells – Small interfering RNAs – T cells


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