Semin Liver Dis 2000; Volume 20(Number 01): 0085-0102
DOI: 10.1055/s-2000-9503
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4663

Distribution of Markers of Hepatitis C Virus Infection Throughout the Body

Eric J. Gowans
  • Sir Albert Sakzewski Virus Research Centre; Royal Children's Hospital; Brisbane, Australia
Further Information

Publication History

Publication Date:
31 December 2000 (online)

 

ABSTRACT

The detection of markers of hepatitis C virus (HCV) infection is complicated by the presence of virus in circulating blood. Consequently, it is necessary to target the negative-strand virus RNA or the nonstructural proteins. This has proved challenging, due to unforeseen difficulties in the specific detection of negative-strand viral RNA. However, recent data suggest that although the liver is the major target organ, the virus may be able to replicate in peripheral blood mononuclear cells, lymph nodes, and pancreas and to a more limited degree in bone marrow cells, thyroid, adrenal glands, and spleen. An analysis of the distribution of virus-infected cells in the liver has proved equally challenging. It is clear from the paucity of data generated by immunoblot and Northern blot hybridization that the level of HCV replication in the liver is very low, and this has necessitated studies to detect the viral RNA and antigens by in situ hybridization and immunohistochemisty, respectively. The results of these studies are quite disparate. Those related to in situ hybridization are nonreproducible and reflect wide disparities in the methodology used by different research workers. The data are often internally inconsistent or are inconsistent with data generated by nucleic acid amplification methods to detect the viral RNA in purified RNA extracts or inconsistent with our current understanding of the virus replication cycle. In contrast, the detection of the viral proteins is more reproducible, and some consensus can be reached. It is clear that frozen sections rather than formalin-fixed paraffin-embedded tissue are preferable. Indeed, it is likely that the use of the latter samples can generate nonspecific positive reactions. Surprisingly, many of the most useful data were derived by the use of polyclonal human antibodies from chronic carriers. HCV proteins were detected in the cytoplasm of infected hepatocytes, often in a punctate granular pattern in some hepatocytes and occasionally in monocytes and other cell types. There is often no correlation between HCV antigen expression and the degree of liver cell injury, although patients with lower levels of antigen expression are more likely to respond to interferon therapy.

KEYWORD

hepatitis C virus - intracellular replication markers - extrahepatic sites

REFERENCES

  • 1 Agnello V, Abel G, Knight G B, Muchmore E. Detection of widespread hepatocyte infection in chronic hepatitis C.  Hepatology . 1998;  28 573-584
    CrossrefPubMedGoogle Scholar
  • 2 Lanford R E, Cahvez D, Chisari F V, 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
    PubMedGoogle Scholar
  • 3 Burleson F G, Chambers T M, Wiedbrauk D L. Virology: A Laboratory Manual. San Diego: Academic Press:
    Google Scholar
  • 4 White D O, Fenner F J. Viral Replication in Medical Virology.  4th ed. San Diego: Academic Press 1994
    Google Scholar
  • 5 Gong Y, Trowbridge R, Macnaughton T B, Westaway E G, Shannon A D, Gowans E J. Characterisation of RNA synthesis during a one-step growth curve and of the replication mechanism of bovine viral diarrhea virus.  J Gen Virol . 1996;  77 2729-2236
    PubMedGoogle Scholar
  • 6 Neumann A U, Lam N P, Dahari H, Gretch D R, Wiley T E, Layden T J, Perelson A S. Hepatitis C viral dyanamics in vivo and the antiviral effect of interferon-alfa therapy.  Science . 1998;  282 103-107
    CrossrefPubMedGoogle Scholar
  • 7 Choo Q-L, Kuo G, Weiner A J, Overby L R, Bradley D W, Houghton M. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome.  Science . 1989;  244 359-362
    CrossrefPubMedGoogle Scholar
  • 8 Kolykhalov A A, Agapov E V, Blight K J, Mihalik K, Feinstone S M, Rice C M. Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA.  Science . 1997;  277 570-574
    CrossrefPubMedGoogle Scholar
  • 9 Negro F, Krawczynski K, Quadri R, Rubbia-Brandt L, Mondelli M, Zarski J-P, Hadengue A. Detection of genomic- and minus-strand of hepatitis C virus RNA in the liver of chronic hepatitis C patients by strand-specific semiquantitative reverse-transcriptase polymerase chain reaction.  Hepatology . 1999;  29 536-542
    CrossrefPubMedGoogle Scholar
  • 10 Nakamoto Y, Kaneko S, Honda M, Unoura M, Cheong J, Harada A, Matsushima K, Kobayashi K, Murakami S. Detection of the putative E2 protein of hepatitis C virus in human liver.  J Med Virol . 1994;  42 374-379
    PubMedGoogle Scholar
  • 11 Tsutsumi M, Urashima S, Takada A, Date T, Tanaka Y. Detection of antigens related to hepatitis C virus RNA encoding the NS5 region in the livers of patients with chronic type C hepatitis.  Hepatology . 1994;  19 265-272
    CrossrefPubMedGoogle Scholar
  • 12 Blight K J, Gowans E J. In situ hybridization and immunohistochemical staining of hepatitis C virus products.  Viral Hepat Rev . 1995;  1 143-155
    PubMedGoogle Scholar
  • 13 Lau J YN, Krawczynski K, Negro F, Gonzalez-Peralta R P. In situ detection of hepatitis C virus-a critical review.  J Hepatol . 1996;  24(Suppl 2) 43-51
    PubMedGoogle Scholar
  • 14 Scheuer P J, Krawczynski K, Dhillon A P. Histopathology and detection of hepatitis C virus in liver.  Semin Immunopathol . 1997;  19 27-45
    PubMedGoogle Scholar
  • 15 Negro F. Detection of hepatitis C virus RNA in liver tissue: an overview.  Ital J Gastroenterol Hepatol . 1998;  30 205-210
    PubMedGoogle Scholar
  • 16 Brahic M, Haase A T. Detection of viral sequences of low reiteration frequency by in situ hybridization.  Proc Natl Acad Sci USA . 1978;  75 6125-6129
    PubMedGoogle Scholar
  • 17 Gerhardt G S, Kawasaki E S, Bancroft F C, Szabo P. Localization of a unique gene by direct hybridization in situ.  Proc Natl Acad Sci USA . 1981;  78 3755-3759
    PubMedGoogle Scholar
  • 18 Gowans E J, Jilbert A R, Burrell C J. Detection of specific DNA and RNA sequences in tissues and cells by in situ hybridization. In: RH Symons, ed. Nucleic Acid Probes Boca Raton, FL: CRC Press, 1989: pp.139-158
    Google Scholar
  • 19 Khromykh A A, Westaway E G. Subgenomic replicons of the Flavivirus Kunjin: construction and applications.  J Virol . 1997;  71 1497-1505
    PubMedGoogle Scholar
  • 20 Honda M, Rijnbrand R, Abell G, Kim D, Lemon S M. Natural variation in translational activities of the 5′nontranslated RNAs of hepatitis C virus genotypes 1a and 1b: evidence for a long-range RNA-RNA interaction outside of the internal ribosome entry site.  J Virol . 1999;  73 4941-4951
    PubMedGoogle Scholar
  • 21 Wang C, Le S Y, Ali N, Siddiqui A. An RNA pseudoknot is an essential structural element of the internal ribosome entry site located with the hepatitis C virus 5′noncoding region.  RNA . 1995;  1 526-537
    PubMedGoogle Scholar
  • 22 Lau J YN, Davis G L. Detection of hepatitis C virus RNA genome in liver tissue by non-isotopic in situ hybridization.  J Med Virol . 1994;  42 268-271
    PubMedGoogle Scholar
  • 23 Lamas E, Baccarini P, Housset C, Kremsdorf D, Brechot C. Detection of hepatitis C virus (HCV) RNA sequences in liver tissue by in situ hybridization.  J Hepatol . 1992;  16 219-223
    CrossrefPubMedGoogle Scholar
  • 24 Tanaka Y, Enomoto N, Kojima S, Tang L, Goto M, Marumo F, Sato C. Detection of hepatitis C virus RNA in the liver by in situ hybridization.  Liver . 1993;  13 203-208
    PubMedGoogle Scholar
  • 25 Yamada G, Nishimoto H, Endou H. Localization of hepatitis C viral RNA and capsid protein in human liver.  Dig Dis Sci . 1993;  38 882-887
    CrossrefPubMedGoogle Scholar
  • 26 Gastaldi M, Massacrier A, Planells R. Detection by in situ hybridization of hepatitis C virus positive and negative RNA strands using digoxigenin-labeled cRNA probes in human liver cells.  J Hepatol . 1995;  23 509-518
    CrossrefPubMedGoogle Scholar
  • 27 Blight K, Trowbridge R, Rowland R, Gowans E. Detection of hepatitis C virus RNA by in situ hybridization.  Liver . 1992;  12 286-289
    PubMedGoogle Scholar
  • 28 Komminoth P, Adams V, Long A A, Roth J, Saremaslani P, Flury R, Schmid M, Heitz P hU. Evaluation of methods for hepatitis C virus detection in archival liver biopsies.  Path Res Pract . 1994;  190 1017-1025
    PubMedGoogle Scholar
  • 29 Nouri Aria T K, Sallie R, Sangar D, Alexander G JM, Smith H, Byrne J, Portmann B, Eddleston A W F L, Williams R. Detection of genomic and intermediate replicative strands of hepatitis C virus in liver tissue by in situ hybridization.  J Clin Invest . 1993;  91 2226-2234
    PubMedGoogle Scholar
  • 30 Loriot M-A, Bronowicki J-P, Lagorce D. Permissiveness of human biliary epithelial cells to infection by hepatitis C virus.  Hepatology . 1999;  29 1587-1595
    CrossrefPubMedGoogle Scholar
  • 31 Endo H, Yamada G, Nakane P K, Tsuji T. Localization of hepatitis C virus RNA in human liver biopsies by in situ hybridization using thymine-thymine dimerized oligo DNA probes: improved method.  Acta Med Okayama . 1992;  46 355-364
    PubMedGoogle Scholar
  • 32 Haruna Y, Hayashi N, Hiramatsu N, Takehara T, Hagiwara H, Sasaki Y, Kasahara A, Fusamoto H, Kamada T. Detection of hepatitis C virus RNA in liver tissues by an in situ hybridization technique.  J Hepatol . 1993;  18 96-100
    CrossrefPubMedGoogle Scholar
  • 33 Negro F, Pacchioni D, Shimizu Y, Miller R H, Bussolati G, Purcell R H, Bonino F. Detection of intrahepatic replication of hepatitis C virus RNA by in situ hybridization and comparison with histopathology.  Proc Natl Acad Sci USA . 1992;  89 2247-2251
    PubMedGoogle Scholar
  • 34 Gosvalez J, Rodriguez-Inigo E, Ramiro-Diaz J L, Bartolome J, Tomas J F, Oliva H, Carreno V. Relative quantitation and mapping of hepatitis C virus by in situ hybridization and digital image analysis.  Hepatology . 1998;  27 1428-1434
    CrossrefPubMedGoogle Scholar
  • 35 Rodriguez-Inigo E, Bartolome J, deLucas S, Manzarbeitia F, Pardo M, Arocena C, Gosalvez J, Oliva H, Carreno V. Histological damage in chronic hepatitis C is not related to the extent of infection in the liver.  Am J Pathol . 1999;  154 1877-1881
    PubMedGoogle Scholar
  • 36 Nuovo G J, Kidonnici K, MacConnell P, Lane B. Intracellular localization of polymerase chain reaction (PCR)-amplified hepatitis C cDNA.  Am J Surg Pathol . 1993;  17 683-690
    PubMedGoogle Scholar
  • 37 Lau G KK, Fang J WS, Wu P C, Davis G L, Lau J YN. Detection of hepatitis C virus genome in formalin-fixed paraffin-embedded liver tissue by in situ reverse transcription polymerase chain reaction.  J Med Virol . 1994;  44 406-409
    PubMedGoogle Scholar
  • 38 Lau G KK, Davis G L, Wu S PC, Gish R G, Balart L A, Lau J YN. Hepatitic expression of hepatitis C virus RNA in chronic hepatitis C: a study by in situ reverse-transcription polymerase chain reaction.  Hepatol . 1996;  23 1318-1323
    PubMedGoogle Scholar
  • 39 Walker F M, Dazza M-C, Dauge M-C, Boucher O, Bedel O C, Henin D, Lehy T. Detection and localization by in situ molecular biology techniques and immunohistochemistry of hepatitis C virus in livers of chronically infected patients.  J Histochem Cytochem . 1998;  46 653-660
    PubMedGoogle Scholar
  • 40 Muratori L. in situ reverse transcriptase-polymerase chain reaction: an innovative tool for hepatitis C virus RNA detection and localization, and for quantification of infected cells.  Eur J Histochem . 1998;  42 133-136
    PubMedGoogle Scholar
  • 41 Sansonno D, Cornacchiulo V, Racanelli V, Dammacco F. In situ simultaneous detection of hepatitis C virus RNA and hepatitis C virus-related antigens in hepatocellular carcinoma.  Cancer . 1997;  80 22-33
    CrossrefPubMedGoogle Scholar
  • 42 Ohishi M, Sakisaka S, Harada M. Detection of hepatitis-C virus and hepatitis-C virus replication in hepatocellular carcinoma by in situ hybridization.  Scand J Gastroenterol . 1999;  34 432-438
    CrossrefPubMedGoogle Scholar
  • 43 Tang L, Tanaka Y, Enomoto N, Marumo F, Sato C. Detection of hepatitis C virus RNA in hepatocellular carcinoma by in situ hybridization.  Cancer . 1995;  76 2211-2216
    PubMedGoogle Scholar
  • 44 Ohsawa M, Itomita Y, Hashimoto M, Kanno H, Aozasa K. Hepatitis C viral genome in a subset of primary hepatitic lymphomas.  Mod Pathol . 1998;  11 471-478
    PubMedGoogle Scholar
  • 45 Booth P J, Stevens D A, Collins M E, Brownlie J. Detection of bovine viral diarrhea virus antigen and RNA in oviduct and granulosa cells of persistently infected cattle.  J Reprod Fertil . 1995;  105 17-24
    PubMedGoogle Scholar
  • 46 Desport M, Collins M E, Brownlie J. Detection of bovine virus diarrhea virus RNA by in situ hybridization with digoxigenin-labelled riboprobes.  Intervirology . 1994;  37 269-276
    PubMedGoogle Scholar
  • 47 Gowans E J, Burrell C J, Jilbert A R, Marmion B P. Cytoplasmic (but not nuclear) hepatitis B virus (HBV) core antigen reflects HBV DNA synthesis at the level of the infected hepatocyte.  Intervirology . 1996;  24 220-225
    PubMedGoogle Scholar
  • 48 Westaway E G. Flavivirus replication strategy.  Adv Virus Res . 1987;  33 45-90
    PubMedGoogle Scholar
  • 49 Westaway E G, Khromykh A A, Mackenzie J M. Nascent flavivirus RNA colocalized in situ with double-stranded RNA in stable replication complexes.  Virology . 1999;  258 108-117
    CrossrefPubMedGoogle Scholar
  • 50 Westaway E G, Mackenzie J M, Kenney M T, Jones M K, Khromykh A A. Ultrastructure of Kunjin virus-infected cells: colocalization of NS1 and NS3 with double-stranded RNA, and of NS2B with NS3, in virus-induced membrane structures.  J Virol . 1997;  71 6650-6661
    PubMedGoogle Scholar
  • 51 Barba G, Harper F, Harada T. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets.  Proc Natl Acad Sci USA . 1997;  94 1200-1205
    CrossrefPubMedGoogle Scholar
  • 52 Harlow E, Lane D. Antibodies: A Laboratory Manual.  New York: Cold Spring Harbor Laboratory 1988
    Google Scholar
  • 53 Krawczynski K, Beach M J, Bradley D W. Hepatitis C virus antigens in hepatocytes: Immunomorphologic detection and identification.  Gastroenterology . 1992;  103 622-629
    PubMedGoogle Scholar
  • 54 Di Bisceglie M A, Hoofnagle J H, Krawczynski K. Changes in hepatitis C virus antigen in liver with antiviral therapy.  Gastroenterology . 1993;  105 858-862
    PubMedGoogle Scholar
  • 55 Vargas V, Krawczynski K, Castells L, Martinez N, Esteban J, Allende H, Esteban R, Guardia J. Recurrent hepatitis C virus infection after liver transplantation: immunohistochemical assessment of the viral antigen.  Liver Transplant Surg . 1998;  4 320-327
    CrossrefPubMedGoogle Scholar
  • 56 Nouri-Aria K T, Sallie R, Mizokami M, Portmann B C, Williams R. Intrahepatic expression of hepatitis C virus antigens in chronic liver disease.  J Pathol . 1995;  175 77-83
    PubMedGoogle Scholar
  • 57 Ballardini G, Groff P, Pontisso P, Giostra F, Francesconi R, Lenzi M, Zauli D, Alberti A, Bianchi F B. Hepatitis C virus (HCV) genotype, tissue HCV antigens, hepatocellular expression of HLA-A, B, C, and intercellular adhesion-1 molecules.  J Clin Invest . 1995;  95 2067-2075
    PubMedGoogle Scholar
  • 58 Ballardini G, Groff P, Giostra F, Francesconi R, Miniero R, Ghetti S, Zauli D, Bianchi F B. Hepatocellular codistribution of c100, c33, c22 and NS5 hepatitis C virus antigens detected by using immunopurified polyclonal spontaneous human antibodies.  Hepatol . 1995;  21 730-734
    CrossrefPubMedGoogle Scholar
  • 59 Gane E J, Naoumov M B, Qian K-P, Mondelli M U, Maertens G, Portmann B C, Lau J YN, Williams R. A longitudinal analysis of hepatitis C virus replication following liver transplantation.  Gastroenterology . 1996;  110 167-177
    CrossrefPubMedGoogle Scholar
  • 60 Blight K, Lesniewski R R, LaBrooy J T, Gowans E J. Detection and distribution of hepatitis C-specific antigens in naturally infected liver.  Hepatology . 1994;  20 553-557
    CrossrefPubMedGoogle Scholar
  • 61 Hiramatsu N, Hayashi N, Haruna Y, Kasahara A, Fusamoto H, Mori C, Fuke I, Okayama H, Kamada T. Immunohistochemical detection of hepatitis C virus-infected hepatocytes in chronic liver disease with monoclonal antibodies to core, envelope and NS3 regions of the hepatitis C virus genome.  Hepatology . 1992;  16 306-311
    PubMedGoogle Scholar
  • 62 Haruna Y, Hayashi N, Kamada T, Hytiroglou P, Thung S N, Gerber M A. Expression of hepatitis C virus in hepatocellular carcinoma.  Cancer . 1994;  73 2253-2258
    PubMedGoogle Scholar
  • 63 Blight K, Lesniewski R, LaBrooy J, Trowbridge R, Gowans E J. Localization of hepatitis C virus proteins in infected liver tissue by immunofluorescence.  Gastroenterol Japon . 1993;  28(Suppl 5) 55-58
    PubMedGoogle Scholar
  • 64 Selby M J, Choo Q-L, Berger K. Expression, identification and subcellular localization of the proteins encoded by the hepatitis C viral genome.  J Gen Virol . 1993;  74 1103-1113
    PubMedGoogle Scholar
  • 65 Yap S-H, Willems M, Van den Oord J. Detection of hepatitis C virus antigen by immuno-histochemical staining: a histological marker of hepatitis C virus infection.  J Hepatol . 1994;  20 275-281
    CrossrefPubMedGoogle Scholar
  • 66 Gonzalez-Peralta R P, Fang J WS, Davis G L. Optimization for the detection of hepatitis C virus antigens in the liver.  J Hepatol . 1994;  20 143-147
    CrossrefPubMedGoogle Scholar
  • 67 Gonzalez-Peralta R P, Fang J WS, Davis G L. Significance of hepatic expression of hepatitis C viral antigens in chronic hepatitis C.  Dig Dis Sci . 1995;  40 2595-2601
    PubMedGoogle Scholar
  • 68 Dries V, Von Both I, Muller M. Detection of hepatitis C virus in paraffin-embedded liver biopsies of patients negative for viral RNA in serum.  Hepatology . 1999;  29 223-229
    CrossrefPubMedGoogle Scholar
  • 69 Sansonno D, Dammacco F. Hepatitis C virus c100 antigen in liver tissue from patients with acute and chronic infection.  Hepatol . 1993;  18 240-245
    CrossrefPubMedGoogle Scholar
  • 70 Blight K, Rowland R, Hall P M, Lesniewski R R, Trowbridge R, LaBrooy J T, Gowans E J. Immunohistochemical detection of the NS4 antigen of hepatitis C virus and its relation to histopathology.  Am J Pathol . 1993;  143 1568-1573
    PubMedGoogle Scholar
  • 71 Gretch D R, Bacchi C E, Corey L. Persistent hepatitis C virus infection after liver transplantation: clinical and virological features.  Hepatol . 1995;  22 1-9
    CrossrefPubMedGoogle Scholar
  • 72 Brody R I, Eng S, Melamed J. Immunohistochemical detection of hepatitis C antigen by monoclonal antibody TORDJI-22 compared with PCR viral detection.  Anat Pathol . 1998;  110 32-37
    PubMedGoogle Scholar
  • 73 Doughty A L, Painter D M, McCaughan G W. Nonspecificity of monoclonal antibody Tordji-22 for the detection of hepatitis C virus in liver transplant recipients with cholestatic hepatitis.  Liver Transplant Surg . 1999;  5 40-45
    CrossrefPubMedGoogle Scholar
  • 74 Willems M, Moshage H, Yap S H. PCR and detection of negative HCV RNA strands.  Hepatol . 1993;  17 526
    CrossrefPubMedGoogle Scholar
  • 75 McGuinness P, Bishop G A, McCaughan G W, Trowbridge R, Gowans E J. False detection of negative strand hepatitis C RNA.  Lancet . 1994;  343 551-552
    CrossrefPubMedGoogle Scholar
  • 76 Lanford R E, Sureau C, Jacob J R, White R, Fuerst T. Demonstration of in vitro infection of chimpanzee hepatocytes with hepatitis C virus using strand specific RT-PCR.  Virology . 1994;  202 606-614
    CrossrefPubMedGoogle Scholar
  • 77 Sangar D V, Carroll A R. A tale of two strands:reverse transcriptase polymerase chain reaction detection of hepatitis C virus replication.  Hepatology . 1998;  28 1173-1176
    CrossrefPubMedGoogle Scholar
  • 78 Zehender G, Meroni L, De Maddalena C, Varchetta S, Monti G, Galli M K. Detection of hepatitis C virus RNA in CD19 peripheral blood mononuclear cells of chronically infected individuals.  J Infect Dis . 1997;  176 1209-1214
    CrossrefPubMedGoogle Scholar
  • 79 Laskus T, Radkowski M, Wang L-F, Vargas H, Rakela J. Search for hepatitis C virus extrahepatic replication sites in patients with acquired immune deficiency syndrome: specific detection of negative-strand viral RNA in various tissues.  Hepatol . 1998;  28 1398-1401
    CrossrefPubMedGoogle Scholar
  • 80 Laskus T, Radkowski M, Wang L-F, Jang S J, Vargas H, Rakela J. Hepatitis C virus quasispecies in patients infected with HIV-1: correlation with extrahepatic viral replication.  Virology . 1998;  248 164-171
    CrossrefPubMedGoogle Scholar
  • 81 Radkowski M, Wang L-F, Vargas H E, Rakela J, Laskus T. Detection of hepatitis C virus replication in peripheral blood mononuclear cells after orthotopic liver transplantation.  Transplantation . 1998;  66 664-666
    CrossrefPubMedGoogle Scholar
  • 82 Laskus T, Radkowski M, Wang L-F, 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
    PubMedGoogle Scholar
  • 83 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
    PubMedGoogle Scholar
  • 84 Maggi F, Fornai C, Vatteroni M L. Differences in hepatitis C virus quasispecies composition between liver, peripheral blood mononuclear cells and plasma.  J Gen Virol . 1997;  79 1521-1525
    PubMedGoogle Scholar
  • 85 Lerat H, Berby F, Trabaud M A, Vidalin O, Major M, Trepo C, Inchauspe G. Specific detection of hepatitis C virus minus-strand RNA in hematopoietic cells.  J Clin Invest . 1996;  97 845-851
    CrossrefPubMedGoogle Scholar
  • 86 Navas S, Martin J H, Quiroga J A, Catillo I, Carreno V. Genetic diverstiy and tissue compartmentalization of the hepatitis C virus genome in blood mononuclear cells, liver, and serum from chronic hepatitis C patients.  J Virol . 1998;  72 1640-1646
    PubMedGoogle Scholar
  • 87 Chang T-T, Young K-C, Yang Y-J, Lei H-Y, Wu H-L. Hepatitis C virus RNA in peripheral blood mononuclear cells: comparing acute and chronic hepatitis C virus infection.  Hepatol . 1996;  23 977-981
    PubMedGoogle Scholar
  • 88 Bouffard P, Hayashi P H, Acevedo R, Levy N, Zeldis J B. Hepatitis C virus is detected in a monocyte/macrophage subpopulation of peripheral blood mononuclear cells of infected patients.  J Infect Dis . 1992;  166 1276-1280
    PubMedGoogle Scholar
  • 89 Muratori L, Giostra F, Cataleta M. Testing for hepatitis C virus sequences in peripheral blood mononuclear cells of patients with chronic hepatitis C in the absence of serum hepatitis C virus RNA.  Liver . 1994;  14 124-128
    PubMedGoogle Scholar
  • 90 Bronowicki J-P, Loriot M-A, Thiers V, Grignon Y, Zignego A L, Brechot C. Hepatitis C virus persistence in human hematopoietic cells injected into SCID mice.  Hepatology . 1998;  28 211-218
    CrossrefPubMedGoogle Scholar
  • 91 Moldvay J, Deny P, Pol S, Brechot C, Lamas E. Detection of hepatitis C virus RNA in peripheral blood mononuclear cells of infected patients by in situ hybridization.  Blood . 1994;  83 269-273
    PubMedGoogle Scholar
  • 92 Sansonno D, Iacobelli A R, Cornacchiulo V, Iodice G, Dammacco F. Detection of hepatitis C virus (HCV) proteins by immunofluorescence and HCV RNA genomic sequences by non-isotopic in situ hybridization in bone marrow and peripheral blood mononuclear cells of chronically HCV-infected patients.  Clin Exp Immunol . 1996;  103 414-421
    PubMedGoogle Scholar
  • 93 Muratori L, Gibellini D, Lenzi M, Cataleta M, Muratori P, Morelli M C, Bianchi F B. Quantification of hepatitis C virus-infected peripheral blood mononuclear cells by in situ reverse transcriptase-polymerase chain reaction.  Blood . 1996;  7 2768-2774
    PubMedGoogle Scholar
  • 94 Hadziyannis S. Nonhepatic manifestations and combined diseases in HCV infection.  Dig Dis Sci . 1996;  41(Suppl) 63S-74S
    PubMedGoogle Scholar
  • 95 Sansonno D, Cornacchiulo V, Iacobelli A R, De Stefano R, Lospalluti M, Dammacco F. Localization of hepatitis C virus antigens in liver and skin tissues of chronic hepatitis C virus-infected patients with mixed cryoglobulinemia.  Hepatol . 1995;  21 305-312
    CrossrefPubMedGoogle Scholar
  • 96 Sansonno D, De Vita S, Cornacchiulo V, Carbone A, Boiocchi M, Dammacco F. Detection and distribution of hepatitis C virus-related proteins in lymph nodes of patients with type II mixed cryoglobulinemia and neoplasia or non-neoplastic lymphoproliferation.  Blood . 1996;  88 4638-4645
    PubMedGoogle Scholar
  • 97 Agnello V, Abel G. Localization of hepatitis C virus in cutaneous vasculitic lesions in patients with type II cryoglobulinemia.  Arthritis Rheum . 1997;  40 2007-2015
    PubMedGoogle Scholar
  • 98 Mangra A, Andriulli A, Zenarola P, Lomuto M, Cascavilla I, Quadri R, Negro F. Lack of hepatitis C virus replication intermediate RNA in diseased skin tissue of chronic hepatitis C patients.  J Med Virol . 1999;  59 277-280
    CrossrefPubMedGoogle Scholar