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Front. Microbiol. | doi: 10.3389/fmicb.2019.01972

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

 Esther Merlini1,  Maddalena Cerrone1, 2, Bonnie van Wilgenburg3,  Leo Swadling3, Elvira S. Cannizzo1, Antonella d'Arminio Monforte1,  Paul Klenerman3 and  Giulia C. Marchetti1*
  • 1University of Milan, Italy
  • 2Chelsea and Westminster Hospital NHS Foundation Trust, United Kingdom
  • 3Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, United Kingdom

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<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/CD39), exhaustion (PD1), and cytolytic activity (granzymeB/perforin). Following PMA/ionomycin and E. coli 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 (p=.001), yet expressed higher perforin (p=0.004) and granzyme B (p=0.002) on CD8+ MAIT cells. Upon E. coli 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+: p=0.002; PD-1+: p=0.030) and with cytolytic potential (perforin+: p<0.0001), yet were poorly responsive to ex vivo stimulation.
A profound gut dysbiosis characterized virally-infected pts, especially HCV+/HIV+ co-infected patients, delineating a Firmicutes-poor/Bacteroidetes-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 ex vivo 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 Firmicutes and Bacteroidetes, 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.

Keywords: Dysbiosis, Gut Microbiota, microbial translocation, HIV infection, HCV infection, MAIT, mucosal-associated invariant T cell

Received: 08 Apr 2019; Accepted: 12 Aug 2019.

Copyright: © 2019 Merlini, Cerrone, van Wilgenburg, Swadling, Cannizzo, d'Arminio Monforte, Klenerman and Marchetti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Giulia C. Marchetti, University of Milan, Milan, 20122, Lombardy, Italy, giulia.marchetti@unimi.it