Persistent gamma delta T-cell dysfunction in chronic HCV infection despite direct-acting antiviral therapy induced cure

J Viral Hepat. 2019 Sep;26(9):1105-1116. doi: 10.1111/jvh.13121. Epub 2019 May 26.


Immune dysfunction is a hallmark of chronic HCV infection and viral clearance with direct antivirals recover some of these immune defects. TCRVγ9Vδ2 T-cell dysfunction in treated HCV patients however is not well studied and was the subject of this investigation. Peripheral blood cells from patients who had achieved sustained virologic response (SVR) or those who had relapsed after interferon-free therapy were phenotyped using flow cytometry. Functional potential of Vγ9Vδ2 T cells was tested by measuring proliferation in response to aminobisphosphonate zoledronic acid, and cytotoxicity against HepG2 hepatoma cell line. TCR sequencing was performed to analyse impact of HCV infection on Vδ2 T-cell repertoire. Vγ9Vδ2 cells from patients were activated and therapy resulted in reduction of CD38 expression on these cells in SVR group. Relapsed patients had Vδ2 cells with persistently activated and terminally differentiated cytotoxic phenotype (CD38+ CD45RA+ CD27- CD107a+ ). Irrespective of outcome with therapy, majority of patients had persistently poor Vδ2 T-cell proliferative response to zoledronate along with lower expression of CD56, which identifies anti-tumour cytotoxic subset, relative to healthy controls. There was no association between the number of antigen reactive Vγ2-Jγ1.2 TCR rearrangements at baseline and levels of proliferation indicating nonresponse to zoledronate is not due to depletion of phosphoantigen responding chains. Thus, HCV infection results in circulating Vγ9Vδ2 T cells with a phenotype equipped for immediate effector function but poor cytokine response and expansion in response to antigen, a functional defect that may have implications for susceptibility for carcinogenesis despite HCV cure.

Keywords: DAA therapy; HCV; hepatocellular carcinoma; zoledronic acid; γδ T cells.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Aged
  • Antiviral Agents / therapeutic use*
  • Cell Proliferation / drug effects
  • Clinical Trials as Topic
  • Cohort Studies
  • Cytokines / immunology
  • Cytotoxicity Tests, Immunologic
  • Female
  • Hep G2 Cells
  • Hepatitis C, Chronic / drug therapy*
  • Hepatitis C, Chronic / immunology*
  • Humans
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Phenotype
  • Receptors, Antigen, T-Cell, gamma-delta
  • Sustained Virologic Response*
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology*
  • Zoledronic Acid / pharmacology


  • Antiviral Agents
  • Cytokines
  • Receptors, Antigen, T-Cell, gamma-delta
  • Zoledronic Acid