Productive replication of hepatitis C virus in perihepatic lymph nodes in vivo: implications of HCV lymphotropism

Gastroenterology. 2006 Apr;130(4):1107-16. doi: 10.1053/j.gastro.2005.12.039.


Background & aims: The pathogenesis of chronic hepatitis C is poorly understood. This study examines the ability of hepatitis C virus (HCV) to infect, replicate in, and produce progeny virus from perihepatic lymph nodes in vivo.

Methods: Lymph node (LN) biopsy specimens were taken from 20 patients with HCV genotype 1 infection and end-stage liver disease and 20 noninfected negative controls. Sections were probed with HCV RNA strand-specific riboprobes and antibodies specific for HCV core and nonstructural region 3 antigens plus B-cell (CD20) and T-cell (CD2) antigens. In a selected case, HCV quasispecies in serum, peripheral blood mononuclear cells, liver, and perihepatic lymph nodes were analyzed by clonal frequency analysis and sequencing.

Results: HCV infection was confirmed in 17 of 20 (85%) of lymph node specimens by in situ hybridization, and HCV replication was confirmed in 50% of cases by detection of HCV replicative intermediate RNA. HCV core and nonstructural 3 antigens were detected in lymph nodes by immunocytochemistry. Infected cell phenotypes were primarily CD20 B cells, although other cell types were positive for HCV replication markers. Quasispecies analysis in one case indicated that 68% of variants circulating in serum were also present in lymphoid tissues, and only 40% of serum variants were identified in liver, documenting a major contribution of lymphoid replication to HCV viremia.

Conclusions: HCV lymphotropism provides new insights into the complex pathobiology of chronic hepatitis C in humans. We demonstrate for the first time a major contribution of extrahepatic HCV replication to circulating virus in serum (viremia).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Antigens, CD20 / analysis
  • B-Lymphocytes / immunology
  • B-Lymphocytes / virology
  • Genetic Variation
  • Genotype
  • Hepacivirus / genetics
  • Hepacivirus / physiology*
  • Hepatitis C Antigens / analysis
  • Hepatitis C, Chronic / pathology
  • Hepatitis C, Chronic / virology*
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Liver*
  • Lymph Nodes / immunology
  • Lymph Nodes / pathology
  • Lymph Nodes / virology*
  • Phenotype
  • Viremia / virology
  • Virus Replication*


  • Antigens, CD20
  • Hepatitis C Antigens