In Chronic Hepatitis C Infection, Myeloid-Derived Suppressor Cell Accumulation and T Cell Dysfunctions Revert Partially and Late After Successful Direct-Acting Antiviral Treatment

Abstract

Chronic HCV infection is characterized by several immunological alterations, such as the accumulation of suppressor cells and of hyperactivated T lymphocytes. However, it is unclear whether direct-acting antiviral (DAA)-mediated HCV clearance restores immune dysfunctions. We performed a phenotypic characterization by flow cytometry of different immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSCs) and T lymphocytes in 168 patients with persistent HCV infection not treated, under DAA therapies and sustained virological responders. Chronic HCV infection prompted the accumulation of M-MDSCs independently of patient and clinical characteristics, and altered their metabolic properties. HCV RNA was undetectable in the majority of patients just after few weeks of DAA therapy, whereas M-MDSC levels normalized only 6 months after therapy. In addition, HCV infection deeply perturbed the T cell compartment since a re-distribution of memory CD4 + and CD8 + T cells was observed at the expenses of naïve cells, and memory T lymphocytes displayed increased activation. Notably, these features were only partially restored by DAA therapies in the CD4, but not in the CD8, compartment as high immune activation levels persisted in the terminally differentiated memory CD8 + T cells even more than 1 year after sustained virological response. Together, these results suggest that successful DAA therapies do not lead to full immunological reconstitution as fast as viral clearance.

Early expansion of myeloid-derived suppressor cells inhibits SARS-CoV-2 specific T-cell response and may predict fatal COVID-19 outcome

“…We identified the PMN-MDSC frequency as an early marker of COVID-19 fatal outcome involved in the inhibition of SARS-CoV-2 specific T-cell response. The increased proportion of circulating MDSCs, mainly described in cancer, is attracting great interest in infectious diseases 18 – 22 Although MDSC typically arise in in peripheral tissues to dampen inflammation and inflammation-induced tissue damage, a detrimental role of this cell population in cancer and infectious diseases has been widely reported 21 , 23 , 24 . We recently found an expansion of PMN-MDSC in the peripheral blood of COVID-19 patients compared to HD, in particular in patients experiencing severe disease 11 , 12 .…”

HPV-Specific Systemic Antibody Responses and Memory B Cells are Independently Maintained up to 6 Years and in a Vaccine-Specific Manner Following Immunization with Cervarix and Gardasil in Adolescent and Young Adult Women in Vaccination Programs in Italy

“…Briefly, whole blood was centrifuged at 2500 rpm (Megafuge 1.0R, Heraeus) for 7 min. to collect plasma, whereas the cellular fraction was loaded on Ficoll density gradient (GE Healthcare) to purify PBMCs, as previously described [29,30]. Plasma was stored at −20 • C and purified PBMCs were suspended in 90% foetal bovine serum (FBS) (Lonza) and 10% DMSO (Sigma-Aldrich) and then preserved in liquid nitrogen until use.…”

Immunological Mechanisms for Hepatocellular Carcinoma Risk after Direct-Acting Antiviral Treatment of Hepatitis C Virus Infection

“…Moreover, the frequency of MDSCs, defined as CD14 - HLA-DR - CD11b + CD33 + cells, correlates with the frequency of Treg cells in HCC [ 55 , 108 ]. HCV RNA was reported to be undetectable in most patients after a few weeks of DAA treatment, and the frequency of M-MDSC cells did not normalize 6 months after the end of the treatment ( Figure 1 ) [ 109 ]. These results suggest that a sustained increase in the frequency of MDSCs in HCV infection may contribute to the occurrence or recurrence of HCC.…”