AUTHOR=Merlini Esther , Cerrone Maddalena , van Wilgenburg Bonnie , Swadling Leo , Cannizzo E. Stefania , d’Arminio Monforte Antonella , Klenerman Paul , Marchetti Giulia 

TITLE=Association Between Impaired Vα7.2+CD161++CD8+ (MAIT) and Vα7.2+CD161-CD8+ T-Cell Populations and Gut Dysbiosis in Chronically HIV- and/or HCV-Infected Patients

JOURNAL=Frontiers in Microbiology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2019.01972

DOI=10.3389/fmicb.2019.01972

ISSN=1664-302X

ABSTRACT=<p>Both HIV and HCV infections feature increased microbial translocation (MT) and gut dysbiosis that affect immune homeostasis and disease outcome. Given their commitment to antimicrobial mucosal immunity, we investigated mucosal-associated invariant T (MAIT) cells and Vα7.2+CD161- T-cell frequency/function and their possible associations with MT and gut dysbiosis, in chronic HIV and/or HCV infections. We enrolled 56 virally infected (VI) patients (pts): 13 HIV+ on suppressive cART (HIV-RNA &lt; 40cp/ml), 13 HCV+ naive to DAA (direct-acting antiviral) anti-HCV agents; 30 HCV+/HIV+ on suppressive cART and naive to anti-HCV. 13 age-matched healthy controls (HC) were enrolled. For Vα7.2+CD161++ and Vα7.2+CD161-CD8+ T cells we assessed: activation (CD69), exhaustion (PD1/CD39), and cytolytic activity (granzymeB/perforin). Following PMA/ionomycin and <italic>Escherichia coli</italic> stimulation we measured intracellular IL17/TNFα/IFNγ. Markers of microbial translocation (Plasma LPS, 16S rDNA, EndoCAb and I-FABP) were quantified. In 5 patients per group we assessed stool microbiota composition by 16S targeted metagenomics sequencing (alpha/beta diversity, relative abundance). Compared to controls, virally infected pts displayed significantly lower circulating Vα7.2+CD161++CD8+ MAIT cells (<italic>p</italic> = 0.001), yet expressed higher perforin (<italic>p</italic> = 0.004) and granzyme B (<italic>p</italic> = 0.002) on CD8+ MAIT cells. Upon <italic>E. coli</italic> stimulation, the residual MAIT cells are less functional particularly those from HIV+/HCV+ patients. Conversely, in virally infected pts, Vα7.2+CD161-CD8+ cells were comparable in frequency, highly activated/exhausted (CD69+: <italic>p</italic> = 0.002; PD-1+: <italic>p</italic> = 0.030) and with cytolytic potential (perforin+: <italic>p</italic> &lt; 0.0001), yet were poorly responsive to <italic>ex vivo</italic> stimulation. A profound gut dysbiosis characterized virally infected pts, especially HCV+/HIV+ co-infected patients, delineating a <italic>Firmicutes</italic>-poor/<italic>Bacteroidetes-</italic>rich microbiota, with significant associations with MAIT cell frequency/function. Irrespective of mono/dual infection, HIV+ and HCV+ patients display depleted, yet activated/cytolytic MAIT cells with reduced <italic>ex vivo</italic> function, suggesting an impoverished pool, possibly due to continuous bacterial challenge. The MAIT cell ability to respond to bacterial stimulation correlates with the presence of <italic>Firmicutes</italic> and <italic>Bacteroidetes</italic>, possibly suggesting an association between gut dysbiosis and MAIT cell function and posing viral-mediated dysbiosis as a potential key player in the hampered anti-bacterial MAIT ability.</p>