Occult infection with hepatitis C virus: Friend or foe

Immunology and Cell Biology

Volumn 90, Issue 8, 2012, Pages 763-773

  Sugden, Peter B ^a   Cameron, Barbara ^a   Bull, Rowena ^a   White, Peter A ^a   Lloyd, Andrew R ^a  

^a UNIVERSITY OF NEW SOUTH WALES   (Australia)

Author keywords

hepatitis C virus; occult infection; PCR

Indexed keywords

ALPHA INTERFERON; CORE PROTEIN; DNA DIRECTED RNA POLYMERASE; GLYCOPROTEIN E1; GLYCOPROTEIN E2; HEPATITIS C ANTIBODY; NONSTRUCTURAL PROTEIN 4A; NONSTRUCTURAL PROTEIN 4B; NONSTRUCTURAL PROTEIN 5A; NONSTRUCTURAL PROTEIN 5B; RIBAVIRIN; RNA DIRECTED DNA POLYMERASE; VIRUS RNA;

ANTIVIRAL THERAPY; CELL STIMULATION; CELLULAR IMMUNITY; CHRONIC LIVER DISEASE; CRYPTOGENIC LIVER DISEASE; DENDRITIC CELL; DIAGNOSTIC ACCURACY; ENZYME IMMUNOASSAY; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOBLOTTING; IMMUNOELECTRON MICROSCOPY; IMMUNOHISTOCHEMISTRY; IMMUNOLOGICAL MEMORY; IN SITU HYBRIDIZATION; LIMIT OF DETECTION; MEDICAL DEVICE; MIXED INFECTION; NONHUMAN; NUCLEIC ACID AMPLIFICATION; NUCLEIC ACID ANALYSIS; OCCULT INFECTION; PERIPHERAL BLOOD MONONUCLEAR CELL; REINFECTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; REVIEW; RNA EXTRACTION; SCREENING TEST; SENSITIVITY AND SPECIFICITY; SEROCONVERSION; VIRAL TROPISM; VIREMIA; VIRUS DETECTION; VIRUS REPLICATION; VIRUS TRANSMISSION;

ANIMALS; ANTIVIRAL AGENTS; DIAGNOSTIC TECHNIQUES AND PROCEDURES; HEPACIVIRUS; HEPATITIS C; HUMANS; RNA, VIRAL; TROPISM;

HEPATITIS C VIRUS;

EID: 84866353046     PISSN: 08189641     EISSN: 14401711     Source Type: Journal    
DOI: 10.1038/icb.2012.20     Document Type: Review

References (142)

1. Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium. J Viral Hepat 1999; 6: 35-47.
2. Seeff LB. Natural history of chronic hepatitis C. Hepatology 2002; 36: S35-S46.
3. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management, and treatment of hepatitis C. Hepatology 2004; 39: 1147-1171.
4. Pawlotsky JM. The results of Phase III clinical trials with telaprevir and boceprevir presented at the Liver Meeting 2010: A new standard of care for hepatitis C virus genotype 1 infection, but with issues still pending. Gastroenterology 2011; 140: 746-754.
5. Elliot LN, Lloyd AR, Ziegler JB, Ffrench RA. Protective immunity against hepatitis C virus infection. Immunol Cell Biol 2006; 84: 239-249.
6. Carreno V, Pardo M, Lopez-Alcorocho JM, Rodriguez-Inigo E, Bartolome J, Castillo I. Detection of hepatitis C virus (HCV) RNA in the liver of healthy, anti HCV antibody positive, serum HCV RNA negative patients with normal alanine aminotransferase levels. J Infect Dis 2006; 194: 53-60.
7. Castillo I, Rodriguez-Inigo E, Lopez-Alcorocho JM, Pardo M, Bartolome J, Carreno V. Hepatitis C virus replicates in the liver of patients who have a sustained response to antiviral treatment. Clin Infect Dis 2006; 43: 1277-1283.
8. FalconAcosta-Rivero V, Shibayama N, Luna-Munoz M, Miranda-Sanchez J, de la Rosa MM, et al. Evidences of hepatitis C virus replication in hepatocytes and perpheral blood mononuclear cells from patients negative for viral RNA in serum. Am J Infect Dis 2005; 1: 34-42.
9. Barril G, Castillo I, Arenas MD, Espinosa M, Garcia-Valdecasas J, Garcia-Fernandez N et al. Occult hepatitis C virus infection among hemodialysis patients. J Am Soc Nephrol 2008; 19: 2288-2292.
10. Castillo I, Pardo M, Bartolome J, Ortiz-Movilla N, Rodriguez-Inigo E, Sd Lucas et al. Occult hepatitis C virus infection in patients in whom the etiology of persistently abnormal results of liver function tests is unknown. J Infect Dis 2004; 189: 7-14.
11. Radkowski M, Gallegos-Orozco JF, Jablonska J, Colby TV, Walewska-Zielecka B, Kubicka J et al. Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology 2005; 41: 106-114.
12. Durand F, Beauplet A, Marcellin P. Evidence of hepatitis C virus viremia without detectable antibody to hepatitis C virus in a blood donor. Ann Intern Med 2000; 133: 74-75.
13. Gruber A, Lundberg LG, Bjorkholm M. Reactivation of chronic hepatitis C after withdrawal of immunosuppressive therapy. J Intern Med 1993; 234: 223-225.
14. Lee WM, Polson JE, Carney DS, Sahin B, Gale M. Reemergence of hepatitis C virus after 8.5 years in a patient with hypogammaglobulinemia: Evidence for an occult viral reservoir. J Infect Dis 2005; 192: 1088-1092.
15. Melisko ME, Fox R, Venook A. Reactivation of hepatitis C virus after chemotherapy for colon cancer. Clin Oncol 2004; 16: 204-205.
16. Abe K, Shikata T, Fujisawa K, Yamauchi M, Matsushita H, Suzuki H et al. Transmission of non-A, non-B hepatitis agent to chimpanzees from patients of epidemic hepatitis. Jpn J Med Sci Biol 1986; 39: 119-127.
17. Bassett SE, Brasky KM, Lanford RE. Analysis of hepatitis C virus-inoculated chimpanzees reveals unexpected clinical profiles. J Virol 1998; 72: 2589-2599.
18. Washburn ML, Bility MT, Zhang L, Kovalev GI, Buntzman A, Frelinger JA et al. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 2011; 140: 1334-1344.
19. Robertson B, Myers G, Howard C, Brettin T, Bukh J, Gaschen B et al. Classification, nomenclature, and database development for hepatitis C virus (HCV) and related viruses: Proposals for standardization. Arch Virol 1998; 143: 2493-2503.
20. Bartenschlager R, Lohmann V. Replication of hepatitis C virus. J Gen Virol 2000; 81: 1631-1648.
21. Lanford R, Chavez D, Chisari F, Sureau C. Lack of detection of negative-strand hepatitis C virus RNA in peripheral blood mononuclear cells and other extrahepatic tissues by the highly strand-specific rTth reverse transcriptase PCR. J Virol 1995; 69: 8079-8083.
22. Quinkert D, Bartenschlager R, Lohmann V. Quantitative analysis of the hepatitis C virus replication complex. J Virol 2005; 79: 13594-13605.
23. Ciesek S, Friesland M, Steinmann J, Becker B, Wedemeyer H, Manns MP et al. How stable is the hepatitis C virus (HCV)? Environmental stability of HCV and its susceptibility to chemical biocides. J Infect Dis 2010; 201: 1859-1866.
24. Zeuzem S, Schmidt J, Lee J, von Wagner M, Teuber G, Roth W. Hepatitis C virus dynamics in vivo: Effect of ribavirin and interferon alfa on viral turnover. Hepatology 1998; 28: 245-252.
25. Bartolome J, Lopez-Alcorocho JM, Castillo I, Rodriguez-Inigo E, Quiroga JA, Palacios R et al. Ultracentrifugation of serum samples allows detection of hepatitis C virus RNA in patients with occult hepatitis C. J Virol 2007; 81: 7710-7715.
26. Castillo I, Rodriguez-Inigo E, Bartolome J, de Lucas S, Ortiz-Movilla N, Lopez-Alcorocho JM et al. Hepatitis C virus replicates in peripheral blood mononuclear cells of patients with occult hepatitis C virus infection. Gut 2005; 54: 682-685.
27. Halfon P, Bourliere M, Ouzan D, Sene D, Saadoun D, Khiri H et al. Occult hepatitis C virus infection revisited with ultrasensitive real-time PCR assay. J Clin Microbiol 2008; 46: 2106-2108.
28. Lanford RE, Sureau C, Jacob JR, White R, Fuerst TR. Demonstration of in vitro infection of chimpanzee hepatocytes with hepatitis C virus using strand-specific RT/PCR. Virology 1994; 202: 606-614.
29. Laskus T, Radkowski M, Wang L, Cianciara J, Vargas H, Rakela J. Hepatitis C virus negative strand RNA is not detected in peripheral blood mononuclear cells and viral sequences are identical to those in serum: A case against extrahepatic replication. J Gen Virol 1997; 78: 2747-2750.
30. White PA, Pan Y, Freeman AJ, Marinos G, Ffrench RA, Lloyd AR et al. Quantification of hepatitis C virus in human liver and serum samples by using LightCycler reverse transcriptase PCR. J Clin Microbiol 2002; 40: 4346-4348.
31. Blight K, Gowans E. In situ hybridisation and immuno-histochemical staining of hepatitis C virus products. Viral Hepat Rev 1995; 1: 143-155.
32. Stiffler JD, Nguyen M, Sohn JA, Liu C, Kaplan D, Seeger C. Focal distribution of hepatitis C virus RNA in infected livers. PLoS ONE 2009; 4: E6661.
33. Blackard JT, Kemmer N, Sherman KE. Extrahepatic replication of HCV: Insights into clinical manifestations and biological consequences. Hepatology 2006; 44: 15-22.
34. Saadoun D, Delluc A, Piette JC, Cacoub P. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol 2008; 20: 23-28.
35. Forton DM, Karayiannis P, Mahmud N, Taylor-Robinson SD, Thomas HC. Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J Virol 2004; 78: 5170-5183.
36. Mellor J, Haydon G, Blair C, Livingstone W, Simmonds P. Low level or absent in vivo replication of hepatitis C virus and hepatitis G virus/GB virus C in peripheral blood mononuclear cells. J Gen Virol 1998; 79: 705-714.
37. Schmidt WN, Wu P, Cederna J, Mitros FA, LaBrecque DR, Stapleton JT. Surreptitious hepatitis C virus (HCV) infection detected in the majority of patients with cryptogenic chronic hepatitis and negative HCV antibody tests. J Infect Dis 1997; 176: 27-33.
38. Blackard JT, Smeaton L, Hiasa Y, Horiike N, Onji M, Jamieson DJ et al. Detection of hepatitis C virus (HCV) in serum and peripheral-blood mononuclear cells from HCVmonoinfected and HIV/HCV-coinfected persons. J Infect Dis 2005; 192: 258-265.
39. Marukian S, Jones CT, Andrus L, Evans MJ, Ritola KD, Charles ED et al. Cell cultureproduced hepatitis C virus does not infect peripheral blood mononuclear cells. Hepatology 2008; 48: 1843-1850.
40. Shimizu YK, Iwamoto A, Hijikata M, Purcell RH, Yoshikura H. Evidence for in vitro replication of hepatitis C virus genome in a human T-cell line. Proc Natl Acad Sci USA 1992; 89: 5477-5481.
41. MacParland SA, Pham TNQ, Guy CS, Michalak TI. Hepatitis C virus persisting after clinically apparent sustained virological response to antiviral therapy retains infectivity in vitro. Hepatology 2009; 49: 1431-1441.
42. Geller SA, Nichols WS, Rojter SE, Chan RCK, Petrovic LM, Vierling JM et al. Hepatitis C virus is not recoverable from liver tissue in cryptogenic cirrhosis: Failure to identify
43. Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC et al. Complete replication of hepatitis C virus in cell culture. Science 2005; 309: 623-626.
44. Fletcher NF, Yang JP, Farquhar MJ, Hu K, Davis C, He Q et al. Hepatitis C virus infection of neuroepithelioma cell lines. Gastroenterology 2010; 139: 1365-1374.
45. Goutagny N, Fatmi A, Ledinghen VD, Penin F, Couzigou P, Inchauspe G et al. Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection. J Infect Dis 2003; 187: 1951-1958.
46. Thongsawat S, Maneekarn N, Kuniholm MH, Pantip C, Thungsuputi A, Lumlertkul D et al. Occult hepatitis C virus infection during an outbreak in a hemodialysis unit in Thailand. J Med Virol 2008; 80: 808-815.
47. Radkowski M, Horban A, Gallegos-Orozco JF, Pawelczyk A, Jablonska J, Wilkinson J et al. Evidence for viral persistence in patients who test positive for anti hepatitis C virus antibodies and have normal alanine aminotransferase levels. J Infect Dis 2005; 191: 1730-1733.
48. Pham TNQ, MacParland SA, Coffin CS, Lee SS, Bursey FR, Michalak TI. Mitogeninduced upregulation of hepatitis C virus expression in human lymphoid cells. J Gen Virol 2005; 86: 657-666.
49. 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.
50. Laskus T, Radkowski M, Piasek A, Nowicki M, Horban A, Cianciara J et al. Hepatitis C virus in lymphoid cells of patients coinfected with human immunodeficiency virus type 1: Evidence of active replication in monocytes/macrophages and lymphocytes. J Infect Dis 2000; 181: 442-448.
51. Laskus T, Radkowski M, Wang L-F, Jang SJ, Vargas H, Rakela J. Hepatitis C virus quasispecies in patients infected with HIV-1: Correlation with extrahepatic viral replication. Virology 1998; 248: 164-171.
52. Deforges S, Evlashev A, Perret M, Sodoyer M, Pouzol S, Scoazec J-Y et al. Expression of hepatitis C virus proteins in epithelial intestinal cells in vivo. J Gen Virol 2004; 85: 2515-2523.
53. Pawlotsky J-M, Lonjon I, Hezode C, Raynard B, Darthuy F, Remire J et al. What strategy should be used for diagnosis of hepatitis C virus infection in clinical laboratories? Hepatology 1998; 27: 1700-1702.
54. Colin C, Lanoir D, Touzet S, Meyaud-Kraemer L, Bailly F, Trepo C et al. Sensitivity and specificity of third-generation hepatitis C virus antibody detection assays: An analysis of the literature. J Viral Hepat 2001; 8: 87-95.
55. Halfon P, Bourliere M, Khiri H, Halimi G, Gerolami V, Feryn JM et al. Serological response to infection with different isolates of hepatitis C virus. J Viral Hepat 2002; 9: 438-442.
56. Cerino A, Bissolati M, Cividini A, Nicosia A, Esumi M, Hayashi N et al. Antibody responses to the hepatitis C virus E2 protein: Relationship to viraemia and prevalence in anti-HCV seronegative subjects. J Med Virol 1997; 51: 1-5.
57. Quiroga JA, Castillo I, Pardo M, Rodriguez-Inigo E, Carreno V. Combined hepatitis C virus (HCV) antigen-antibody detection assay does not improve diagnosis for seronegative individuals with occult HCV infection. J Clin Microbiol 2006; 44: 4559-4560.
58. Pawlotsky J-M. Use and interpretation of virological tests for hepatitis C. Hepatology 2002; 36: S65-S73.
59. Quiroga JA, Castillo I, Llorente S, Bartolome J, Barril G, Carreno V. Identification of serologically silent occult hepatitis C virus infection by detecting immunoglobulin G antibody to a dominant HCV core peptide epitope. J Hepatol 2009; 50: 256-263.
60. Mishiro S, Hoshi Y, Yoshikawa A, Gotanda T, Tsuda F, Takeda K et al. Non-A, non-B hepatitis specific antibodies directed at host-derived epitope: Implication for an autoimmune process. Lancet 1990; 336: 1400-1403.
61. Quiroga JA, Castillo I, Bartolome J, Carreno V. Serum immunoglobulin G antibodies to the GOR autoepitope are present in patients with occult hepatitis C virus (HCV) infection despite lack of HCV-specific antibodies. Clin Vaccine Immunol 2007; 14: 1302-1306.
62. Francis Jr T. On the Doctrine of Original Antigenic Sin. Proc Am Philos Soc 1960; 104: 572-578.
63. Michalak TI, Pham TN. Anti-HCV core antibody: A potential new marker of occult and otherwise serologically silent HCV infection. J Hepatol 2009; 50: 244-246.
64. George SL, Gebhardt J, Klinzman D, Foster MB, Patrick KD, Schmidt WN et al. Hepatitis C virus viremia in HIV-infected individuals with negative HCV antibody tests. J Acquir Immune Defic Syndr 2002; 31: 154-162.
65. Hanuka N, Sikuler E, Tovbin D, Mostoslavsky M, Hausman M, Orgel M et al. Hepatitis C virus infection in renal failure patients in the absence of anti-hepatitis C virus antibodies. J Viral Hepat 2002; 9: 141-145.
66. Larke B, Hu YW, Krajden M, Scalia V, Byrne SK, Boychuk LR et al. Acute nosocomial HCV infection detected by NAT of a regular blood donor. Transfusion (Paris) 2002; 42: 759-765.
67. Roth WK, Weber M, Seifried E. Feasibility and efficacy of routine PCR screening of blood donations for hepatitis C virus, hepatitis B virus, and HIV-1 in a blood-bank setting. Lancet 1999; 353: 359-363.
68. Hitzler WE, Runkel S. Routine HCV PCR screening of blood donations to identify early HCV infection in blood donors lacking antibodies to HCV. Transfusion (Paris) 2001; 41: 333-337.
69. Legler TJ, Riggert J, Simson G, Wolf C, Humpe A, Munzel U et al. Testing of individual blood donations for HCV RNA reduces the residual risk of transfusiontransmitted HCV infection. Transfusion (Paris) 2000; 40: 1192-1197.
70. Hyland C, Seed CR, Kiely P, Parker S, Cowley N, Bolton W. Follow-up of six blood donors highlights the complementary role and limitations of hepatitis C virus antibody and nucleic acid amplification tests. Vox Sang 2003; 85: 1-8.
71. Alvarez M, Planelles D, Vila E, Montoro J, Franco E. Prolonged hepatitis C virus seroconversion in a blood donor, detected by HCV antigen test in parallel with HCV RNA. Vox Sang 2004; 86: 266-267.
72. Santantonio T, Sinisi E, Guastadisegni A, Casalino C, Mazzola M, Gentile A et al. Natural course of acute hepatitis C: A long-term prospective study. Dig Liver Dis 2003; 35: 104-113.
73. Meyer MF, Wedemeyer H, Monazahian M, Dreesman J, Manns MP, Lehmann M. Prevalence of hepatitis C in a German prison for young men in relation to country of birth. Epidemiol Infect 2007; 135: 274-280.
74. Post JJ, Pan Y, Freeman AJ, Harvey CE, White PA, Palladinetti P et al. Clearance of hepatitis C viremia associated with cellular immunity in the absence of seroconversion in the hepatitis C incidence and transmission in prisons study cohort. J Infect Dis 2004; 189: 1846-1855.
75. Shata MT, Tricoche N, Perkus M, Tom D, Brotman B, McCormack P et al. Exposure to low infective doses of HCV induces cellular immune responses without consistently detectable viremia or seroconversion in chimpanzees. Virology 2003; 314: 601-616.
76. Rodger AJ, Roberts S, Lanigan A, Bowden S, Brown T, Crofts N. Assessment of longterm outcomes of community-acquired hepatitis C infection in a cohort with sera stored from 1971 to 1975. Hepatology 2000; 32: 582-587.
77. Takaki A, Wiese M, Maertens G, Depla E, Seifert U, Liebetrau A et al. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat Med 2000; 6: 578-582.
78. Zibert A, Meisel H, Kraas W, Schulz A, Jung G, Roggendorf M. Early antibody response against hypervariable region 1 is associated with acute self-limiting infections of hepatitis C virus. Hepatology 1997; 25: 1245-1249.
79. Genesca J, Esteban JI, Quer J, Viladomiu LL, Gonzalez A, Esteban R et al. Hepatitis C virus markers in patients with acute post-transfusion hepatitis treated with interferon alfa-2b. Gut 1993; 34: S62-S63.
80. Simon N, Courouce AM, Lemarrec N, Trepo C, Ducamp S. A twelve year natural history of hepatitis C virus infection in hemodialyzed patients. Kidney Int 1994; 46: 504-511.
81. Goffin E, Pirson Y, Cornu C, Geubel A, Squifflet JP, van Ypersele de Strihou C. Outcome of HCV infection after renal transplantation. Kidney Int 1994; 45: 551-555.
82. Seeff LB, Hollinger FB, Alter HJ, Wright EC, Cain CM, Buskell ZJ et al. Long-term mortality and morbidity of transfusion-associated non-A, non-B, and type C hepatitis: A National Heart, Lung, and Blood Institute collaborative study. Hepatology 2001; 33: 455-463.
83. Pawlotsky J-M. Molecular diagnosis of viral hepatitis. Gastroenterology 2002; 122: 1554-1568.
84. White PA, Li Z, Zhai X, Marinos G, Rawlinson WD. Mixed viral infection identified using Heteroduplex Mobility Analysis (HMA). Virology 2000; 271: 382-389.
85. Compton J. Nucleic acid sequence-based amplification. Nature 1991; 350: 91-92.
86. Urdea MS, Horn T, Fultz TJ, Anderson M, Running JA, Hamren S et al. Branched DNA amplification multimers for the sensitive, direct detection of human hepatitis virusesNucleic Acids Symp Ser 1991: 197-200.
87. Saldanha J, Lelie N, Heath A. Establishment of the first international standard for nucleic acid amplification technology (NAT) assays for HCV RNA. Vox Sang 1999; 76: 149-158.
88. Barbeau JM, Goforth J, Caliendo AM, Nolte FS. Performance characteristics of a quantitative TaqMan hepatitis C virus RNA analyte-specific reagent. J Clin Microbiol 2004; 42: 3739-3746.
89. Martinot-Peignoux M, Khiri H, Leclere L, Maylin S, Marcellin P, Halfon P. Clinical performances of two real-time PCR assays and bDNA/TMA to early monitor treatment outcome in patients with chronic hepatitis C. J Clin Virol 2009; 46: 216-221.
90. MacParland SA, Pham TNQ, Gujar SA, Michalak TI. De novo infection and propagation of wild-type Hepatitis C virus in human T lymphocytes in vitro. J Gen Virol 2006; 87: 3577-3586.
91. Lanford R, Chavez D. Strand-specific rTth RT-PCR for the analysis of HCV replication. In: Lau YN (ed). Hepatitis C Protocols. Humana Press: Totowa, NJ, 1998: 471-481.
92. Ruttimann C, Cotoras M, Zaldia J, Vicuna R. DNA polymerases from the extremely thermophilic bacterium Thermus thermophilus HB-8. Eur J Biochem 1985; 149: 41-46.
93. Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M et al. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol 2003; 41: 4531-4536.
94. Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Laboratory Press, New York, 1992.
95. Barker E, Bossart K, Levy J. Differential effects of CD28 costimulation on HIV production by CD4 cells. J Immunol 1998; 161: 6223-6227.
96. Kadkol SS, Gage WR, Pasternack GR. In situ hybridization - theory and practice. Mol Diagn 1999; 4: 169-183.
97. Veerapu NS, Raghuraman S, Liang TJ, Heller T, Rehermann B. Sporadic reappearance of minute amounts of hepatitis C virus RNA after successful therapy stimulates cellular immune responses. Gastroenterology 2011; 140: 676-685. e671.
98. Agnello V, Abel G, Knight GB, Muchmore E. Detection of widespread hepatocyte infection in chronic hepatitis C. Hepatology 1998; 28: 573-584.
99. Reichard O, Glaumann H, FrydE'n A, Norkrans G, Schvarcz R, S○ nnerborg A et al. Twoyear biochemical, virological, and histological follow-up in patients with chronic hepatitis C responding in a sustained fashion to interferon alfa-2b treatment. Hepatology 1995; 21: 918-922.
100. Shindo M, Arai K, Sokawa Y, Okuno T. Hepatic hepatitis C virus RNA as a predictor of a long-term response to interferon-alpha therapy. Ann Intern Med 1995; 122: 586-591.
101. De Mitri MS, Morsica G, Chen CH, Mele L, Baccarini P, Chianese R et al. Complete eradication of hepatitis C virus after interferon treatment for chronic hepatitis C. Ital J Gastroenterol Hepatol 1997; 29: 255-261.
102. Teramura KMD, Fukuda AMD, Kobayashi HMD, Yoshimoto SMD, Kawashima HMD, Ohsawa NMD. Virus elimination and histologic improvement in patients with chronic hepatitis C treated with interferon alpha. J Clin Gastroenterol 1997; 25: 346-351.
103. Marcellin P, Boyer N, Gervais A, Martinot M, Pouteau M, Castelnau C et al. Long-Term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon-alpha therapy. Ann Intern Med 1997; 127: 875-881.
104. Larghi A, Tagger A, Crosignani A, Ribero ML, Bruno S, Portera G et al. Clinical significance of hepatic HCV RNA in patients with chronic hepatitis C demonstrating long-term sustained response to interferon-alpha therapy. J Med Virol 1998; 55: 7-11.
105. Lau DT, Kleiner DE, Ghany MG, Park Y, Schmid P, Hoofnagle JH. 10-year follow-up after interferon-alpha therapy for chronic hepatitis C. Hepatology 1998; 28: 1121-1127.
106. McHutchison JG, Poynard T, Esteban-Mur R, Davis GL, Goodman ZD, Harvey J et al. Hepatic HCV RNA before and after treatment with interferon alone or combined with ribavirin. Hepatology 2002; 35: 688-693.
107. Bizollon T, Ahmed SNS, Radenne S, Chevallier M, Chevallier P, Parvaz P et al. Long term histological improvement and clearance of intrahepatic hepatitis C virus RNA following sustained response to interferon-ribavirin combination therapy in liver transplanted patients with hepatitis C virus recurrence. Gut 2003; 52: 283-287.
108. Tsuda N, Yuki N, Mochizuki K, Nagaoka T, Yamashiro M, Omura M et al. Long-term clinical and virological outcomes of chronic hepatitis C after successful interferon therapy. J Med Virol 2004; 74: 406-413.
109. Moreno M, Perez-Alvarez R, Rodrigo L, Perez-Lupez R, Suarez-Leiva P. Long-term evolution of serum and liver viral markers in patients treated for chronic hepatitis C and sustained response. J Viral Hepat 2006; 13: 28-33.
110. Maylin S, Martinot-Peignoux M, Moucari R, Boyer N, Ripault M-P, Cazals-Hatem D et al. Eradication of hepatitis C virus in patients successfully treated for chronic hepatitis C. Gastroenterology 2008; 135: 821-829.
111. Koch R. Ueber den augenblicklichen Stand der bakteriologischen Choleradiagnose. Med Microbiol Immunol (Berl) 1893; 14: 319-338.
112. Verslype C, Nevens F, Sinelli N, Clarysse C, Pirenne J, Depla E et al. Hepatic immunohistochemical staining with a monoclonal antibody against HCV-E2 to evaluate antiviral therapy and reinfection of liver grafts in hepatitis C viral infection. J Hepatol 2003; 38: 208-214.
113. Aytaman A, Kaufman M, Terrault NA. Management of posttransplant hepatitis C infection. Curr Opin Organ Transplant 2010; 15: 301-309.
114. De Marco L, Gillio-Tos A, Fiano V, Ronco G, Krogh V, Palli D et al. Occult HCV Infection: An Unexpected Finding in a Population Unselected for Hepatic Disease. PLoS ONE 2009; 4: E8128.
115. Quiroga JA, Llorente S, Castillo I, Rodriguez-Inigo E, Pardo M, Carreno V. Cellular immune responses associated with occult hepatitis C virus infection of the liver. J Virol 2006; 80: 10972-10979.
116. Quiroga JA, Llorente S, Castillo I, Rodriguez-Inigo E, Lopez-Alcorocho JM, Pardo M et al. Virus-specific T-cell responses associated with hepatitis C virus (HCV) persistence in the liver after apparent recovery from HCV infection. J Med Virol 2006; 78: 1190-1197.
117. Pham TN, Mercer SE, Michalak TI. Chronic hepatitis C and persistent occult hepatitis C virus infection are characterized by distinct immune cell cytokine expression profiles. J Viral Hepat 2009; 16: 547-556.
118. Freeman AJ, Ffrench RA, Post JJ, Harvey CE, Gilmour SJ, White PA et al. Prevalence of production of virus-specific interferon-gamma among seronegative hepatitis C-resistant subjects reporting injection drug use. J Infect Dis 2004; 190: 1093-1097.
119. Lloyd AR, Jagger E, Post JJ, Crooks L-A, Rawlinson WD, Hahn YS et al. Host and viral factors in the immunopathogenesis of primary hepatitis C virus infection. Immunol Cell Biol 2007; 85: 24-32.
120. Castillo I, Bartolome J, Quiroga JA, Barril G, Carreno V. Hepatitis C virus infection in the family setting of patients with occult hepatitis C. J Med Virol 2009; 81: 1198-1203.
121. Kamal SM, Amin A, Madwar M, Graham CS, He Q, Al Tawil A et al. Cellular immune responses in seronegative sexual contacts of acute hepatitis C patients. J Virol 2004; 78: 12252-12258.
122. Post J, Ratnarajah S, Lloyd A. Immunological determinants of the outcomes from primary hepatitis C infection. Cell Mol Life Sci 2009; 66: 733-756.
123. Hu K-Q. Occult hepatitis B virus infection and its clinical implications. J Viral Hepat 2002; 9: 243-257.
124. Mulrooney-Cousins PM, Michalak TI. Persistent occult hepatitis B virus infection: Experimental findings and clinical implications. World J Gastroenterol 2007; 13: 5682-5686.
125. Awerkiew S, Daumer M, Reiser M, Wend UC, Pfister H, Kaiser R et al. Reactivation of an occult hepatitis B virus escape mutant in an anti-HBs positive, anti-HBc negative lymphoma patient. J Clin Virol 2007; 38: 83-86.
126. Kojima H, Abei M, Takei N, Mukai Y, Hasegawa Y, Iijima T et al. Fatal reactivation of hepatitis B virus following cytotoxic chemotherapy for acute myelogenous leukemia: Fibrosing cholestatic hepatitis. Eur J Haematol 2002; 69: 101-104.
127. Kusumoto S, Tanaka Y, Ueda R, Mizokami M. Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy. J Gastroenterol 2011; 46: 9-16.
128. Lew Y, Michalak TI. In vitro and in vivo infectivity and pathogenicity of the lymphoid cell-derivied woodchuck hepatitis virus. J Virol 2001; 75: 1770-1782.
129. Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H, de Jong YP et al. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 2009; 457: 882-886.
130. Sainz Jr B, Barretto N, Martin DN, Hiraga N, Imamura M, Hussain S et al. Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nat Med 2012; 18: 281-285.
131. Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, Zona L et al. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med 2011; 17: 589-595.
132. Micheloud D, Gonzalez-Nicolas J, Berenguer J, Lorente R, Miralles P, Lopez J et al. CD81 expression in peripheral blood lymphocytes before and after treatment with interferon and ribavirin in HIV/HCV coinfected patients. HIV Med 2009; 11: 161-169.
133. Zhu P, Liu X, Treml L, Cancro M, Freedman B. Mechanisms and regulatory function of CpG signaling via scavenger receptor B1 in primary B cells. J Biol Chem2009; 284: 22878-22887.
134. Sakamoto A, Sugamoto Y, Tokunaga Y, Yoshimuta T, Hayashi K, Konno T et al. Expression profiling of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. J Int Med Res 2011; 39: 522-527.
135. Sarhan MA, Pham TN, Chen AY, Michalak TI. Hepatitis C Virus Infection of Human T Lymphocytes is Mediated by CD5. J Virol 2012.
136. Farci P, Shimoda A, Wong D, Cabezon T, De Gioannis D, Strazzera A et al. Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein. Proc Natl Acad Sci USA 1996; 93: 15394-15399.
137. Shimizu YK, Hijikata M, Iwamoto A, Alter HJ, Purcell RH, Yoshikura H. Neutralizing antibodies against hepatitis C virus and the emergence of neutralization escape mutant viruses. J Virol 1994; 68: 1494-1500.
138. Everson GT, Trotter J, Forman L, Kugelmas M, Halprin A, Fey B et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology 2005; 42: 255-262.
139. Forns X, Garcia-Retortillo M, Serrano T, Feliu A, Suarez F, de la Mata M et al. Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation. J Hepatol 2003; 39: 389-396.
140. Pham ST, Bull RA, Bennett JM, Rawlinson WD, Dore GJ, Lloyd AR et al. Frequent multiple hepatitis C virus infections among injection drug users in a prison setting. Hepatology 2010; 52: 1564-1572.
141. Viswanatha DS, Dogan A. Hepatitis C virus and lymphoma. J Clin Pathol 2007; 60: 1378-1383.
142. Dutton RW, Bradley LM, Swain SL. T cell memory. Annu Rev Immunol 1998; 16: 201-223.