Hierarchical assessment of host factors influencing the spontaneous resolution of hepatitis C infection
Hepatitis C virus (HCV) infection is associated with chronic liver disease, resulting in cirrhosis and hepatocellular carcinoma. Approximately 20% of HCV infections are spontaneously resolved. Here, we assessed the hierarchical relevance of host factors contributing to viral clearance.
DNA samples from 40 resolved infections and 40 chronic HCV patients paired by age were analyzed. Bivariate analysis was performed to rank the importance of each contributing factor in spontaneous HCV clearance.
Interestingly, 63.6% of patients with resolved infections exhibited the protective genotype CC for SNP rs12979860. Additionally, 59.3% of patients with resolved infections displayed the protective genotype TT/TT for SNP ss469415590. Moreover, a ranking of clearance factors was estimated. In order of importance, the IL28B CC genotype (OR 0.197, 95% CI 0.072–0.541) followed by the INFL4 TT/TT genotype (OR 0.237, 95% CI 0.083–0.679), and female gender (OR 0.394, 95% CI 0.159–0.977) were the main predictors for clearance of HCV infection.
HCV clearance is multifactorial and the contributing factors display a hierarchical order. Identifying all elements playing role in HCV clearance is of the most importance for HCV-related disease management. Dissecting the relevance of each contributing factor will certainly improve our understanding of the pathogenesis of HCV infection.
KeywordsHepatitis C HCV MAVS SNP rs12979860 IL28B
PJSP, PR, LMGR, GV, and BMC wrote of the manuscript. PJSP, PR, and MLN conceived and designed the experiments; PJSP, BMC, VCM, PCRR, LRC, and STQA performed the experiments; RMF, RMTG, GFS, CRV, and PSN performed the management of samples collection and patients’ data; PJSP, PR, LMGR, BMC, and JAC analyzed the data.
This work was supported by Foundation for Research Support of the State of São Paulo (FAPESP - 2014/22198-0) and the Brazilian National Council for Scientific and Technological Development (CNPq - 2015/34857; 2010/15686).
Compliance with ethical standards
The project was approved by the in-house Ethics Committee of Sao Paulo State University (IBILCE-UNESP, São José do Rio Preto) (No. 049/09), and all participants signed an informed consent form.
Conflict of interest
The authors declare that they have no conflict of interest.
- 3.Takamizawa A, Mori C, Fuke I, Manabe S, Murakami S, Fujita J, Onishi E, Andoh T, Yoshida I, Okayama H (1991) Structure and organization of the hepatitis C virus genome isolated from human carriers. J Virol 65(3):1105–1113Google Scholar
- 4.Hijikata M, Mizushima H, Akagi T, Mori S, Kakiuchi N, Kato N, Tanaka T, Kimura K, Shimotohno K (1993) Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol 67(8):4665–4675Google Scholar
- 5.Kiyosawa K, Sodeyama T, Tanaka E, Gibo Y, Yoshizawa K, Nakano Y, Furuta S, Akahane Y, Nishioka K, Purcell RH, Alter HJ (1990) Interrelationship of blood transfusion, non-a, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 12(4 Pt 1):671–675CrossRefGoogle Scholar
- 12.Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’hUigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M (2009) Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461(7265):798–801CrossRefGoogle Scholar
- 20.Lin R, Lacoste J, Nakhaei P, Sun Q, Yang L, Paz S, Wilkinson P, Julkunen I, Vitour D, Meurs E, Hiscott J (2006) Dissociation of a MAVS/IPS-1/VISA/Cardif-IKKepsilon molecular complex from the mitochondrial outer membrane by hepatitis C virus NS3-4A proteolytic cleavage. J Virol 80(12):6072–6083CrossRefGoogle Scholar
- 25.Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M (2009) Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 41(10):1105–1109CrossRefGoogle Scholar
- 26.Honda M, Sakai A, Yamashita T, Nakamoto Y, Mizukoshi E, Sakai Y, Yamashita T, Nakamura M, Shirasaki T, Horimoto K, Tanaka Y, Tokunaga K, Mizokami M, Kaneko S, Hokuriku Liver Study Group (2010) Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C. Gastroenterology 139(2):499–509CrossRefGoogle Scholar
- 27.Prokunina-Olsson L, Muchmore B, Tang W, Pfeiffer RM, Park H, Dickensheets H, Hergott D, Porter-Gill P, Mumy A, Kohaar I, Chen S, Brand N, Tarway MA, Liu L, Sheikh F, Astemborski J, Bonkovsky HL, Edlin BR, Howell CD, Morgan TR, Thomas DL, Rehermann B, Donnelly RP, O'Brien TR (2013) A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet 45(2):164–171CrossRefGoogle Scholar
- 33.Vernon SD, Unger ER, Williams D (2000) Comparison of human papillomavirus detection and typing by cycle sequencing, line blotting, and hybrid capture. J Clin Microbiol 38(2):651–655Google Scholar
- 47.Wu R, Chi X, Wang X, Sun H, Lv J, Gao X, Yu G, Kong F, Xu H, Hua R, Jiang J, Sun B, Zhong J, Pan Y, Niu J (2016) IFNL4 ss469415590 polymorphism contributes to treatment decisions in patients with chronic hepatitis C virus genotype 1b, but not 2a, infection. Infect Genet Evol 39:132–140CrossRefGoogle Scholar
- 49.Real LM, Neukam K, Herrero R, Guardiola JM, Reiberger T, Rivero-Juarez A, Salazar J, Mandorfer M, Merino D, Soriano V, Rivero A, Macías J, Pineda JA, Caruz A (2014) IFNL4 ss469415590 variant shows similar performance to rs12979860 as predictor of response to treatment against hepatitis C virus genotype 1 or 4 in Caucasians. PLoS One 9(4):e95515CrossRefGoogle Scholar
- 53.Terrault NA (2002) Sexual activity as a risk factor for hepatitis C. Hepatology 36(5 Suppl 1):S99–S105Google Scholar
- 57.Vogel M, Deterding K, Wiegand J, Grüner NH, Baumgarten A, Jung MC, Manns MP, Wedemeyer H, Rockstroh JK, German Hepatitis Group, Hep‐Net (2009) Initial presentation of acute hepatitis C virus (HCV) infection among HIV-negative and HIV-positive individuals-experience from 2 large German networks on the study of acute HCV infection. Clin Infect Dis 49(2):317–319 author reply 319CrossRefGoogle Scholar
- 60.van de Laar T, Pybus O, Bruisten S, Brown D, Nelson M, Bhagani S, Vogel M, Baumgarten A, Chaix ML, Fisher M, Gőtz H, Matthews GV, Neifer S, White P, Rawlinson W, Pol S, Rockstroh J, Coutinho R, Dore GJ, Dusheiko GM, Danta M (2009) Evidence of a large, international network of HCV transmission in HIV-positive men who have sex with men. Gastroenterology 136(5):1609–1617CrossRefGoogle Scholar
- 62.Ingiliz P, Krznaric I, Stellbrink HJ, Knecht G, Lutz T, Noah C, Stocker H, Obermeier M, Dupke S, Boesecke C, Rockstroh JK, Baumgarten A, Hoffmann C (2014) Multiple hepatitis C virus (HCV) reinfections in HIV-positive men who have sex with men: no influence of HCV genotype switch or interleukin-28B genotype on spontaneous clearance. HIV Med 15(6):355–361CrossRefGoogle Scholar