Digestive Diseases and Sciences

, Volume 63, Issue 5, pp 1237–1242 | Cite as

Persistence of Circulating Hepatitis C Virus Antigens-Specific Immune Complexes in Patients with Resolved HCV Infection

  • Ke-Qin Hu
  • Wei Cui
Original Article



Our recent study indicated the possible presence of detectable hepatitis C virus antigens (HCV-Ags) after denaturation of sera with resolved HCV (R-HCV) infection. The present study determined and characterized persistent HCV-Ags-specific immune complexes (ICs) in these patients.


Sixty-eight sera with R-HCV and 34 with viremic HCV (V-HCV) infection were tested for free and IC-bound HCV-Ags using HCV-Ags enzyme immunoassay (EIA), the presence of HCV-Ags-specific ICs by immunoprecipitation and Western blot (IP–WB), HCV ICs containing HCV virions using IP and HCV RNA RT-PCR, and correlation of HCV ICs with clinical presentation in these patients.


Using HCV-Ags EIA, we found 57.4% of sera with R-HCV infection were tested positive for bound, but not free HCV-Ags. Using pooled or individual anti-HCV E1/E2, cAg, NS3, NS4b, and/or NS5a to precipitate HCV-specific-Ags, we confirmed persistent HCV-Ags ICs specific to various HCV structural and non-structural proteins not only in V-HCV infection, but also in R-HCV infection. Using IP and HCV RNA PCR, we then confirmed the presence of HCV virions within circulating ICs in V-HCV, but not in R-HCV sera. Multivariable analysis indicated significant and independent associations of persistent circulating HCV-Ags-specific ICs with both age and the presence of cirrhosis in patients with R-HCV infection.


Various HCV-Ag-specific ICs, but not virions, persist in 57.4% of patients who had spontaneous or treatment-induced HCV clearance for 6 months to 20 years. These findings enriched our knowledge on HCV pathogenesis and support further study on its long-term clinical relevance, such as extrahepatic manifestation, transfusion medicine, and hepatocarcinogenesis.


Hepatitis C virus (HCV) HCV infection Hepatitis C virus antigens (HCV-Ags) HCV core antigen (HCVcAg) HCV immune complexes (HCV ICs) 



Hepatitis C virus


Chronic hepatitis C


Sustained virologic response


Viremic HCV infection


Resolved HCV infection


HCV RNA reverse transcription polymerase chain reaction


HCV core antigen


HCV antigens enzyme immunoassay




Immunoprecipitation and Western blot assays





The authors thank John M. Vierling., M.D., for discussion about data interpretation and critical review of the manuscript.

Author’s contributions

KQH conceived the concept of the entire present study, searched the literature, designed study, analyzed and interpreted the data, and led manuscript writing. WC participated in literature search, performed the experiments, analyzed data, and was involved in manuscript preparation.


This was an institutionally supported investigator-initiated study. There was no external funding.

Compliance with ethical standards

Conflict of interest

Dr. Hu is on the speakers’ bureau for Abbvie, Gilead Sciences Inc., and Merck, and consultant for DiligenMed, Inc. Dr. Cui has no disclosure.


  1. 1.
    Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol. 2014;61:S45–S57.CrossRefPubMedGoogle Scholar
  2. 2.
    Hanafiah KM, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57:1333–1342.CrossRefGoogle Scholar
  3. 3.
    Westbrook RH, Dusheiko G. Natural history of hepatitis C. J Hepatol. 2013;61:S58–S68.CrossRefGoogle Scholar
  4. 4.
    AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus. Hepatology. 2015;62:932–954.CrossRefGoogle Scholar
  5. 5.
    Gutierrez JA, Lawitz EJ, Poordad F. Interferon-free, direct-acting antiviral therapy for chronic hepatitis C. J Viral Hepal. 2015;22:861–870.CrossRefGoogle Scholar
  6. 6.
    van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308:2584–2593.CrossRefPubMedGoogle Scholar
  7. 7.
    Lohmann V. Hepatitis C virus RNA replication. Curr Top Microbiol Immunol. 2013;369:167–198.PubMedGoogle Scholar
  8. 8.
    Choo SH, So HS, Cho JM, Ryu WS. Association of hepatitis C virus particles with immunoglobulin: a mechanism for persistent infection. J Gen Virol. 1995;76:2337–2341.CrossRefPubMedGoogle Scholar
  9. 9.
    Stokes MB. Immune complex glomerulonephritis in patients with hepatitis C. Saudi J Kidney Dis Transpl. 2000;11:396–404.PubMedGoogle Scholar
  10. 10.
    Sansonno D, Lauletta G, Nisi L, et al. Non-enveloped HCV core protein as constitutive antigen of cold-precipitable immune complexes in type II mixed cryoglobulinaemia. Clin Exp Immunol. 2003;133:275–282.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect Dis. 2005;5:227–236.CrossRefPubMedGoogle Scholar
  12. 12.
    Tsai JF, Jeng JE, Chang WY, Ho MS, Lin ZY, Tsai JH. Circulating immune complexes in chronic hepatitis C. Clin Immunol Immunopathol. 1995;75:39–44.CrossRefPubMedGoogle Scholar
  13. 13.
    Fujita N, Kaito M, Tanaka H, et al. Hepatitis C virus free-virion and immune-complex dynamics during interferon therapy with and without ribavirin in genotype-1b chronic hepatitis C patients. J Viral Hepat. 2006;13:190–198.CrossRefPubMedGoogle Scholar
  14. 14.
    Fujita N, Kaito M, Takeo M, et al. Different hepatitis C virus dynamics of free-virions and immune-complexes after initiation of interferon-alpha in patients with chronic hepatitis C. J Hepatol. 2003;39:1013–1019.CrossRefPubMedGoogle Scholar
  15. 15.
    Laperche S, Le Marrec N, Simon N, et al. A new HCV core antigen assay based on disassociation of immune complexes: an alternative to molecular biology in diagnosis of early HCV infection. Transfusion. 2003;43:958–962.CrossRefPubMedGoogle Scholar
  16. 16.
    Hu K-Q, Cui W. A highly specific and sensitive hepatitis C virus antigens enzyme immunoassay (HCV-Ags EIA) for one-step diagnosis of HCV infection. Hepatology. 2016;64:415–424.CrossRefPubMedGoogle Scholar
  17. 17.
    Hu K-Q, Cui W. Application of a novel hepatitis C virus antigens enzyme immunoassay (HCV-Ags EIA) for one-step diagnosis of active HCV infection using urine specimens. Accepted by 2015 AASLD annual meeting, San Francisco.Google Scholar
  18. 18.
    Cui W, Yu CH, Hu KQ. In vitro and in vivo effects and mechanisms of celecoxib-induced growth inhibition of human hepatocellular carcinoma cells. Clin Cancer Res. 2005;11:8213–8221.CrossRefPubMedGoogle Scholar
  19. 19.
    Pham TNQ, MacParland SA, Mulrooney PM, Cooksley H, Naoumov NV, Michalak TI. Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol. 2004;78:5867–5874.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of GI/HepatologyUniversity of California, Irvine, School of MedicineOrangeUSA

Personalised recommendations