Skip to main content

HCV and Blood Cells: How Can We Distinguish Infection from Association?

  • Chapter
  • First Online:
HCV Infection and Cryoglobulinemia
  • 699 Accesses

Abstract

The liver is the primary target of hepatitis C virus (HCV) infection. However, HCV RNA and protein are often observed to associate with B cells and other blood cells. Are these cells truly infected, and if so, does the infection lead to B cell abnormalities? Not all investigators agree. This chapter discusses our recommendations for a rigorous evaluation of the potential roles of blood cells as sites of HCV infection. The detection of HCV RNA and protein should be combined with evaluations of whether levels of these markers are sensitive to potent antiviral compounds that block HCV infection in liver cells. RNA quantitation should include documentation of sensitivity and specificity as well as a number of critical controls. Similarly, reports of protein detection should include documentation of the specificity of the antibodies used, and particularly of the frequency of antigen-positive cells relative to the number of HCV genomes detected. B cells, like other blood cells, do not express all of the cellular factors believed to be required for HCV entry or productive infection. Thus, a number of significant questions must be addressed before we understand whether, and how, infection of B cells contributes to the pathogenesis of mixed cryoglobulinemia.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Lanford RE, Chavez D, Chisari FV et al (1995) 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 69:8079–8083

    PubMed  CAS  Google Scholar 

  2. Marukian S, Jones CT, Andrus L et al (2008) Cell culture-produced hepatitis C virus does not infect peripheral blood mononuclear cells. Hepatology 48:1843–1850

    Article  PubMed  Google Scholar 

  3. Tellinghuisen TL, Evans MJ, von Hahn T et al (2007) Studying hepatitis C virus: making the best of a bad virus. J Virol 81:8853–8867

    Article  PubMed  CAS  Google Scholar 

  4. Zehender G, Meroni L, De Maddalena C et al (1997) Detection of hepatitis C virus RNA in CD19 peripheral blood mononuclear cells of chronically infected patients. J Infect Dis 176:1209–1214

    Article  PubMed  CAS  Google Scholar 

  5. Lerat H, Rumin S, Habersetzer F et al (1998) In vivo tropism of hepatitis C virus genomic sequences in hematopoietic cells: influence of viral load, viral genotype, and cell phenotype. Blood 91:3841–3849

    PubMed  CAS  Google Scholar 

  6. Mellor J, Haydon G, Blair C et al (1998) 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 79(Pt 4):705–714

    PubMed  CAS  Google Scholar 

  7. Fornasieri A, Bernasconi P, Ribero ML et al (2000) Hepatitis C virus (HCV) in lymphocyte subsets and in B lymphocytes expressing rheumatoid factor cross-reacting idiotype in type II mixed cryoglobulinaemia. Clin Exp Immunol 122:400–403

    Article  PubMed  CAS  Google Scholar 

  8. Ducoulombier D, Roque-Afonso AM, Di Liberto G et al (2004) Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes. Hepatology 39:817–825

    Article  PubMed  Google Scholar 

  9. Baré P, Massud I, Parodi C et al (2005) Continuous release of hepatitis C virus (HCV) by peripheral blood mononuclear cells and B-lymphoblastoid cell-line cultures derived from HCV-infected patients. J Gen Virol 86:1717–1727

    Article  PubMed  Google Scholar 

  10. Pham TN, Macparland SA, Coffin CS et al (2005) Mitogen-induced upregulation of hepatitis C virus expression in human lymphoid cells. J Gen Virol 86:657–666

    Article  PubMed  CAS  Google Scholar 

  11. Pal S, Sullivan DG, Kim S et al (2006) Productive replication of hepatitis C virus in perihepatic lymph nodes in vivo: implications of HCV lymphotropism. Gastroenterology 130:1107–1116

    Article  PubMed  Google Scholar 

  12. Sansonno D, Tucci FA, Lauletta G et al (2007) Hepatitis C virus productive infection in mononuclear cells from patients with cryoglobulinaemia. Clin Exp Immunol 147:241–248

    Article  PubMed  CAS  Google Scholar 

  13. Pham TN, King D, Macparland SA et al (2008) Hepatitis C virus replicates in the same immune cell subsets in chronic hepatitis C and occult infection. Gastroenterology 134:812–822

    Article  PubMed  CAS  Google Scholar 

  14. Sung VM, Shimodaira S, Doughty AL et al (2003) Establishment of B-cell lymphoma cell lines persistently infected with hepatitis C virus in vivo and in vitro: the apoptotic effects of virus infection. J Virol 77:2134–2146

    Article  PubMed  CAS  Google Scholar 

  15. Pham TN, MacParland SA, Mulrooney PM et al (2004) Hepatitis C virus persistence after spontaneous or treatment-induced resolution of hepatitis C. J Virol 78:5867–5874

    Article  PubMed  CAS  Google Scholar 

  16. Goutagny N, Fatmi A, De Ledinghen V et al (2003) Evidence of viral replication in circulating dendritic cells during hepatitis C virus infection. J Infect Dis 187:1951–1958

    Article  PubMed  Google Scholar 

  17. Laporte J, Bain C, Maurel P et al (2003) Differential ­distribution and internal translation efficiency of hepatitis C virus quasispecies present in dendritic and liver cells. Blood 101:52–57

    Article  PubMed  CAS  Google Scholar 

  18. Rodrigue-Gervais IG, Jouan L, Beaule G et al (2007) Poly(I:C) and lipopolysaccharide innate sensing functions of circulating human myeloid dendritic cells are affected in vivo in hepatitis C virus-infected patients. J Virol 81:5537–5546

    Article  PubMed  CAS  Google Scholar 

  19. Coquillard G, Patterson BK (2009) Determination of hepatitis C virus-infected, monocyte lineage reservoirs in individuals with or without HIV coinfection. J Infect Dis 200:947–954

    Article  PubMed  Google Scholar 

  20. Boisvert J, He XS, Cheung R et al (2001) Quantitative analysis of hepatitis C virus in peripheral blood and liver: replication detected only in liver. J Infect Dis 184:827–835

    Article  PubMed  CAS  Google Scholar 

  21. Radkowski M, Gallegos-Orozco JF, Jablonska J et al (2005) Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C. Hepatology 41:106–114

    Article  PubMed  Google Scholar 

  22. Inokuchi M, Ito T, Uchikoshi M et al (2009) Infection of B cells with hepatitis C virus for the development of lymphoproliferative disorders in patients with chronic hepatitis C. J Med Virol 81:619–627

    Article  PubMed  CAS  Google Scholar 

  23. Tuplin A, Wood J, Evans DJ et al (2002) Thermodynamic and phylogenetic prediction of RNA secondary structures in the coding region of hepatitis C virus. RNA 8:824–884

    Article  PubMed  CAS  Google Scholar 

  24. You S, Rice CM (2008) 3′ RNA elements in hepatitis C virus replication: kissing partners and long poly(U). J Virol 82:184–195

    Article  PubMed  CAS  Google Scholar 

  25. Lukavsky PJ (2009) Structure and function of HCV IRES domains. Virus Res 139:166–171

    Article  PubMed  CAS  Google Scholar 

  26. Lerat H, Berby F, Trabaud MA et al (1996) Specific detection of hepatitis C virus minus strand RNA in hematopoietic cells. J Clin Invest 97:845–851

    Article  PubMed  CAS  Google Scholar 

  27. Gosert R, Egger D, Lohmann V et al (2003) Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. J Virol 77:5487–5492

    Article  PubMed  CAS  Google Scholar 

  28. Rouillé Y, Helle F, Delgrange D et al (2006) Subcellular localization of hepatitis C virus structural proteins in a cell culture system that efficiently replicates the virus. J Virol 80:2832–2841

    Article  PubMed  Google Scholar 

  29. Targett-Adams P, Boulant S, McLauchlan J (2008) Visualization of double-stranded RNA in cells supporting hepatitis C virus RNA replication. J Virol 82:2182–2195

    Article  PubMed  CAS  Google Scholar 

  30. Miyanari Y, Atsuzawa K, Usuda N et al (2007) The lipid droplet is an important organelle for hepatitis C virus production. Nat Cell Biol 9:1089–1097

    Article  PubMed  CAS  Google Scholar 

  31. Lindenbach BD, Evans MJ, Syder AJ et al (2005) Complete replication of hepatitis C virus in cell culture. Science 309:623–626

    Article  PubMed  CAS  Google Scholar 

  32. Heathcote EJ (2007) Antiviral therapy: chronic hepatitis C. J Viral Hepat 14(Suppl 1):82–88

    Article  PubMed  Google Scholar 

  33. Zeuzem S (2008) Interferon-based therapy for chronic ­hepatitis C: current and future perspectives. Nat Clin Pract Gastroenterol Hepatol 5:610–622

    Article  PubMed  CAS  Google Scholar 

  34. Manns MP, Foster GR, Rockstroh JK et al (2007) The way forward in HCV treatment – finding the right path. Nat Rev Drug Discov 6:991–1000

    Article  PubMed  CAS  Google Scholar 

  35. Burlone ME, Budkowska A (2009) Hepatitis C virus cell entry: role of lipoproteins and cellular receptors. J Gen Virol 90:1055–1070

    Article  PubMed  CAS  Google Scholar 

  36. Bartosch B, Cosset FL (2006) Cell entry of hepatitis C virus. Virology 348:1–12

    Article  PubMed  CAS  Google Scholar 

  37. Brazzoli M, Bianchi A, Filippini S et al (2008) CD81 is a central regulator of cellular events required for hepatitis C virus infection of human hepatocytes. J Virol 82:8316–8329

    Article  PubMed  CAS  Google Scholar 

  38. Gottwein JM, Scheel TK, Jensen TB et al (2009) Development and characterization of hepatitis C virus genotype 1–7 cell culture systems: role of CD81 and scavenger receptor class B type I and effect of antiviral drugs. Hepatology 49:364–377

    Article  PubMed  CAS  Google Scholar 

  39. Evans MJ, von Hahn T, Tscherne DM et al (2007) Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446:801–805

    Article  PubMed  CAS  Google Scholar 

  40. Ploss A, Evans MJ, Gaysinskaya VA et al (2009) Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature 457:882–886

    Article  PubMed  CAS  Google Scholar 

  41. Stamataki Z, Shannon-Lowe C, Shaw J et al (2009) Hepatitis C virus association with peripheral blood B lymphocytes potentiates viral infection of liver-derived hepatoma cells. Blood 113:585–593

    Article  PubMed  CAS  Google Scholar 

  42. Zheng A, Yuan F, Li Y et al (2007) Claudin-6 and claudin-9 function as additional coreceptors for hepatitis C virus. J Virol 81:12465–12471

    Article  PubMed  CAS  Google Scholar 

  43. McKeating JA, Zhang LQ, Logvinoff C et al (2004) Diverse hepatitis C virus glycoproteins mediate viral infection in a CD81 dependent manner. J Virol 78:8496–8505

    Article  PubMed  CAS  Google Scholar 

  44. Bartosch B, Dubuisson J, Cosset F-L (2003) Infectious hepatitis C virus pseudo-particles containing functional E1-E2 envelope protein complexes. J Exp Med 197:633–642

    Article  PubMed  CAS  Google Scholar 

  45. Jopling CL, Yi M, Lancaster AM et al (2005) Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science 309:1577–1581

    Article  PubMed  CAS  Google Scholar 

  46. Randall G, Panis M, Cooper JD et al (2007) Cellular cofactors affecting hepatitis C virus infection and replication. Proc Natl Acad Sci USA 104:12884–12889

    Article  PubMed  CAS  Google Scholar 

  47. Chang J, Guo JT, Jiang D et al (2008) Liver-specific microRNA miR-122 enhances the replication of hepatitis C virus in nonhepatic cells. J Virol 82:8215–8223

    Article  PubMed  CAS  Google Scholar 

  48. Lanford RE, Hildebrandt-Eriksen ES, Petri A et al (2010) Therapeutic silencing of microRNA-122 in primates with chronic hepatitis C virus infection. Science 327(5962):198–201, Epub 2009 Dec 3

    Article  PubMed  CAS  Google Scholar 

  49. Jopling CL, Norman KL, Sarnow P (2006) Positive and negative modulation of viral and cellular mRNAs by liver-specific microRNA miR-122. Cold Spring Harb Symp Quant Biol 71:369–376

    Article  PubMed  CAS  Google Scholar 

  50. Syed G, Amako Y, Siddiqui A (2010) Hepatitis C virus hijacks host lipid metabolism. Trends Endocrinol Metab 21(1):33–40, Epub 2009 Oct 23

    Article  PubMed  CAS  Google Scholar 

  51. Andre P, Komurian-Pradel F, Deforges S et al (2002) Characterization of low- and very-low-density hepatitis C virus RNA-containing particles. J Virol 76:6919–6928

    Article  PubMed  CAS  Google Scholar 

  52. Nielsen SU, Bassendine MF, Burt AD et al (2006) Association between hepatitis C virus and very-low-density lipoprotein (VLDL)/LDL analyzed in iodixanol density gradients. J Virol 80:2418–2428

    Article  PubMed  CAS  Google Scholar 

  53. Nielsen SU, Bassendine MF, Martin C et al (2008) Characterization of hepatitis C RNA-containing particles from human liver by density and size. J Gen Virol 89:2507–2517

    Article  PubMed  CAS  Google Scholar 

  54. Gibbons GF, Wiggins D, Brown AM et al (2004) Synthesis and function of hepatic very-low-density lipoprotein. Biochem Soc Trans 32:59–64

    Article  PubMed  CAS  Google Scholar 

  55. Huang H, Sun F, Owen DM et al (2007) Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins. Proc Natl Acad Sci USA 104:5848–5853

    Article  PubMed  CAS  Google Scholar 

  56. Benga WJ, Krieger SE, Dimitrova M et al (2010) Apolipoprotein E interacts with hepatitis C virus nonstructural protein 5A and determines assembly of infectious particles. Hepatology 51:43–53

    Article  PubMed  CAS  Google Scholar 

  57. Gastaminza P, Cheng G, Wieland S et al (2008) Cellular determinants of hepatitis C virus assembly, maturation, degradation, and secretion. J Virol 82:2120–2129

    Article  PubMed  CAS  Google Scholar 

  58. Chang KS, Jiang J, Cai Z et al (2007) Human apolipoprotein E is required for infectivity and production of hepatitis C virus in cell culture. J Virol 81:13783–13793

    Article  PubMed  CAS  Google Scholar 

  59. Jiang J, Luo G (2009) Apolipoprotein E but not B is required for the formation of infectious hepatitis C virus particles. J Virol 83:12680–12691

    Article  PubMed  CAS  Google Scholar 

  60. Yao H, Ye J (2008) Long chain acyl-CoA synthetase 3-mediated phosphatidylcholine synthesis is required for assembly of very low density lipoproteins in human hepatoma Huh7 cells. J Biol Chem 283:849–854

    Article  PubMed  CAS  Google Scholar 

  61. Lindenbach BD, Meuleman P, Ploss A et al (2006) Cell culture-grown hepatitis C virus is infectious in vivo and can be recultured in vitro. Proc Natl Acad Sci USA 103:3805–3809

    Article  PubMed  CAS  Google Scholar 

  62. Zehender G, De Maddalena C, Bernini F et al (2005) Compartmentalization of hepatitis C virus quasispecies in blood mononuclear cells of patients with mixed cryoglobulinemic syndrome. J Virol 79:9145–9156

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lynn B. Dustin .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Italia

About this chapter

Cite this chapter

Dustin, L.B., Rice, C.M. (2012). HCV and Blood Cells: How Can We Distinguish Infection from Association?. In: Dammacco, F. (eds) HCV Infection and Cryoglobulinemia. Springer, Milano. https://doi.org/10.1007/978-88-470-1705-4_6

Download citation

  • DOI: https://doi.org/10.1007/978-88-470-1705-4_6

  • Published:

  • Publisher Name: Springer, Milano

  • Print ISBN: 978-88-470-1704-7

  • Online ISBN: 978-88-470-1705-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics