Maintenance of Th1 hepatitis C virus (HCV)-specific responses in individuals with acute HCV who achieve sustained virological clearance after treatment

Authors


  • Protocol Steering Committee members: John Kaldor (NCHECR), Gregory Dore (NCHECR), Gail Matthews (NCHECR), Pip Marks (NCHECR), Andrew Lloyd (UNSW), Margaret Hellard (Burnet Institute, Vic.), Paul Haber (University of Sydney), Rose Ffrench (Burnet Institute, Vic.), Peter White (UNSW), William Rawlinson (UNSW), Carolyn Day (University of Sydney), Ingrid van Beek (Kirketon Road Centre), Geoff McCaughan (Royal Prince Alfred Hospital), Annie Madden (Australian Injecting and Illicit Drug Users League, ACT), Kate Dolan (UNSW), Geoff Farrell (Canberra Hospital, ACT), Nick Crofts (Burnet Institute, VIC), William Sievert (Monash Medical Centre, Vic.), David Baker (407 Doctors).
  • NCHECR ATAHC Research Staff: John Kaldor, Gregory Dore, Gail Matthews, Pip Marks, Barbara Yeung, Brian Acraman, Kathy Petoumenos, Janaki Amin, Carolyn Day, Anna Doab, Jason Grebely, Therese Carroll.
  • Burnet Institute Research Staff: Margaret Hellard, Oanh Nguyen, Sally von Bibra.
  • Immunovirology Laboratory Research Staff: UNSW Pathology—Andrew Lloyd, Suzy Teutsch, Hui Li, Alieen Oon, Barbara Cameron.
  • SEALS—William Rawlinson, Brendan Jacka, Yong Pan.
  • Burnet Institute Laboratory, Vic.—Rose Ffrench, Jacqueline Flynn, Kylie Goy.
  • Clinical Site Principal Investigators: Gregory Dore, St Vincent's Hospital, NSW; Margaret Hellard, The Alfred Hospital, Infectious Disease Unit, Vic.; David Shaw, Royal Adelaide Hospital, SA; Paul Haber, Royal Prince Alfred Hospital; Joe Sasadeusz, Royal Melbourne Hospital, Vic.; Darrell Crawford, Princess Alexandra Hospital, Qld; Ingrid van Beek, Kirketon Road Centre; Nghi Phung, Nepean Hospital; Jacob George, Westmead Hospital; Mark Bloch, Holdsworth House GP Practice; David Baker, 407 Doctors; Brian Hughes, John Hunter Hospital; Lindsay Mollison, Fremantle Hospital; Stuart Roberts, The Alfred Hospital, Gastroenterology Unit, Vic.; William Sievert, Monash Medical Centre, Vic.; Paul Desmond, St Vincent's Hospital, Vic.
  • Conflict of interest statement: No author has a commercial or other association that might pose a conflict of interest.
  • Previous presentations: None.
  • Author affiliations: No author has changed their affiliation since completion of the study.
  • Financial support: This study was funded by NIH IROIDA 15999-01. JF was supported by an NHMRC PhD Dora Lush scholarship and MH was supported by NHMRC and VicHealth Fellowships. RF was supported by NHMRC Industry Fellowship. GD, WR, and AL were supported by NHMRC Practitioner Fellowships.

Abstract

Background and Aim

T-cell responses against hepatitis C are believed to be critical in achieving both natural and treatment-induced clearance. However, rapid clearance of antigen with early treatment of primary infection may result in reduced or poorly sustained cellular immunity. This study longitudinally examined Th1 and Th2 hepatitis C virus (HCV)-specific cytokine production and T-cell effector function from subjects enrolled in the Australian Trial in Acute Hepatitis C comparing three groups: treatment-induced clearance (sustained virological response [SVR]), treatment non-response, and untreated spontaneous clearance.

Methods

HCV-specific T-cell responses were characterized by HCV peptide ELISpot, in vitro cytokine production, and T-cell flow cytometry assays.

Results

Treated subjects with a sustained virological response (SVR) displayed a better maintenance of HCV-specific Th1 responses compared to treatment non-responders (higher interferon [IFN]-γ and interleukin (IL)-2 magnitude at week 24, broader IFN-γ responses at weeks 24 and 48, P < 0.05) and significantly increased IFN-γ responses between screening and week 48 (magnitude P = 0.026, breadth P = 0.009). Treatment-induced viral clearance was also associated with a trend toward decreased IL-10 responses (screening to week 48, P = 0.070), higher expression of CD45RO (P = 0.042) and CD38 (P = 0.088) on CD4+ T cells, and higher IFN-γR expression (CD56+IFN-γR+ P = 0.033) compared to treatment non-responders. Untreated subjects with viral clearance also displayed high magnitude and broad HCV-specific IFN-γ and IL-2 responses early in infection; however, IFN-γ responses were not as well maintained compared to treated subjects with a SVR (week 48 magnitude, breadth P = 0.064).

Conclusion

Treatment-induced viral clearance of recent HCV infection is associated with maintenance of HCV-specific Th1 responses.

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