Journal
HEPATOLOGY COMMUNICATIONS
Volume 2, Issue 4, Pages 364-375Publisher
JOHN WILEY & SONS LTD
DOI: 10.1002/hep4.1166
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Funding
- National Institute of Allergy and Infectious Diseases [RO1AI120622]
- National Institute of Diabetes and Digestive and Kidney Diseases [RO1DK106491]
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R01AI127463, R01AI120622] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T32DK067009, R01DK106491] Funding Source: NIH RePORTER
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Chronic hepatitis C virus (HCV) infection is characterized by dysregulated natural killer (NK) cell responses. NKs play a critical role in achieving sustained responses to interferon (IFN)-alpha-based therapy. Rapid sustained HCV-RNA clearance is now achieved with direct-acting antivirals (DAAs). Studies of patients receiving first-wave DAAs suggest NK functional restoration. Here, we investigate the effect of mainstream DAA treatment on NKs. We collected a prospective cohort of male HCV genotype 1-infected patients treated with ledipasvir/sofosbuvir (n = 22). Peripheral blood was obtained at treatment start, week 2 (W2), W4, W8, and W12 of treatment and 12 weeks posttreatment. Flow cytometry was used to characterize NK responses to therapy. Mean baseline viral load was 1.75 million IU/mL. All subjects rapidly cleared virus and remained HCV RNA-negative posttreatment. No change was seen in total NK levels; however, the frequency of immature NKs (clusters of differentiation [CD]56(bright)) decreased by W2 and was maintained throughout the study. Phenotypic changes were evident by W2/W4, coincident with rapid viral clearance. At W2, T-cell immunoglobulin and mucin-domain containing-3 and CD161 were significantly increased, returning to pretreatment levels by W12. Some changes were not evident until late (W12 or posttreatment). Down-regulation of several activation markers, including NKp30 and tumor necrosis factor-related apoptosis-inducing ligand, was observed at W12 and sustained posttreatment. No difference was observed in IFN-gamma production or cytokine-mediated killing of NK-sensitive cell line K562 posttreatment compared to pretreatment. Conclusion: Our phenotype data suggest transient activation followed by dampening of NK cell activity to pretreatment levels. The NK response to ledipasvir/sofosbuvir is not universal in a homogeneous patient cohort. More studies are needed to elucidate the roles of NK cells in IFN-free regimens, which will have implications for protection from re-infection and fibrosis progression.
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