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

Immune dysfunction is a hallmark of chronic HCV infection and viral clearance with direct antivirals recover some of these immune defects. TCRV gamma 9V delta 2 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 V gamma 9V delta 2 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 V delta 2 T-cell repertoire. V gamma 9V delta 2 cells from patients were activated and therapy resulted in reduction of CD38 expression on these cells in SVR group. Relapsed patients had V delta 2 cells with persistently activated and terminally differentiated cytotoxic phenotype (CD38(+)CD45RA(+)CD27(-)CD107a(+)). Irrespective of outcome with therapy, majority of patients had persistently poor V delta 2 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 V gamma 2-J gamma 1.2 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 V gamma 9V delta 2 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.