Memory re-differentiation and reduced lymphocyte activation in chronic HCV-infected patients receiving direct-acting antivirals.
Recently, the treatment of HCV has advanced significantly due to the introduction of direct-acting antivirals (DAAs). Studies using interferon (IFN)-containing regimens failed to consistently show restoration of immunologic responses. Therefore, IFN-free DAA formulations provide a unique opportunity to dissect the immunologic effect of HCV cure. This study investigates the restoration of the immune compartment as a consequence of rapid viral clearance in patients successfully treated with DAAs and in the absence of IFN and ribavirin. Here, we evaluate the immunologic changes that occurred following DAA-mediated HCV cure. Peripheral blood from nineteen previously treatment-naïve patients with chronic HCV genotype 1a/1b who received an IFN and ribavirin-free regimen of daclatasvir, asunaprevir and BMS-791325 was evaluated. Immune reconstitution occurs in patients in whom HCV was successfully eradicated via DAA therapy. Restoration of the CD4(+) T-cell compartment in the peripheral blood and a re-differentiation of the T lymphocyte memory compartment resulted in a more effector memory cell population and a reduction in expression in the co-inhibitory molecule TIGIT in bulk T lymphocytes. Furthermore, we observed a partial reversal of the exhausted phenotype in HCV-specific CD8(+) T cells and a dampening of the activation state in peripheral NK cells. Collectively, our data provide the groundwork for dissecting the effect of DAA therapy on the immune system and identifying novel mechanisms by which chronic HCV infection exerts immunosuppressive effects on T cells through the recently described co-inhibitory molecule TIGIT.
Department of Medicine, Division of GI/Heaptology, University of Colorado-Denver, Aurora, CO, USA.
M A
MA
Burchill
Department of Medicine, Division of GI/Heaptology, University of Colorado-Denver, Aurora, CO, USA.
L
L
Golden-Mason
Bristol-Myers Squibb, Exploratory Clinical and Translational Research, Lawrenceville, NJ, USA.
M
M
Wind-Rotolo
Department of Medicine, Division of GI/Heaptology, University of Colorado-Denver, Aurora, CO, USA.
H R
HR
Rosen
D000998:Antiviral Agents / Q000627:therapeutic use; D001552:Benzazepines / Q000627:therapeutic use*; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002219:Carbamates; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D007156:Immunologic Memory / Q000276:immunology; D007211:Indoles / Q000627:therapeutic use*; D007546:Isoquinolines / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D011759:Pyrrolidines; D011971:Receptors, Immunologic / Q000096:biosynthesis; D013449:Sulfonamides / Q000627:therapeutic use*; D014633:Valine / Q000031:analogs & derivatives; D019562:Viral Load / Q000187:drug effects
C587012:8-cyclohexyl-N-((dimethylamino)sulfonyl)-1,1a,2,12b-tetrahydro-11-methoxy-1a-((3-methyl-3,8-diazabicyclo(3.2.1)oct-8-yl)carbonyl)cycloprop(d)indolo(2,1-a)(2)benzazepine-5-carboxamide; D000998:Antiviral Agents; D001552:Benzazepines; D017252:CD3 Complex; D002219:Carbamates; D007093:Imidazoles; D007211:Indoles; D007546:Isoquinolines; D011759:Pyrrolidines; D011971:Receptors, Immunologic; D013449:Sulfonamides; C534712:TIGIT protein, human; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir
HCV; NK cells; T cells; T-cell immunoreceptor with Ig and ITIM domains; direct-acting antiviral (DAA)