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

被引:117
作者
Pal, S
Sullivan, DG
Kim, S
Lai, KKY
Kae, J
Cotler, SJ
Carithers, RL
Wood, BL
Perkins, JD
Gretch, DR
机构
[1] Univ Washington, Med Ctr, Seattle, WA 98195 USA
[2] Univ Calif Irvine, Dept Dev & Cell Biol, Irvine, CA 92717 USA
[3] Rush Presbyterian St Lukes Med Ctr, Sect Hepatol, Chicago, IL 60612 USA
[4] Univ Washington, Med Ctr, Dept Med, Seattle, WA 98195 USA
[5] Univ Washington, Med Ctr, Dept Surg, Seattle, WA 98195 USA
关键词
D O I
10.1053/j.gastro.2005.12.039
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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).
引用
收藏
页码:1107 / 1116
页数:10
相关论文
共 36 条
  • [1] Efficient replication of hepatitis C virus genotype 1a RNAs in cell culture
    Blight, KJ
    McKeating, JA
    Marcotrigiano, J
    Rice, CM
    [J]. JOURNAL OF VIROLOGY, 2003, 77 (05) : 3181 - 3190
  • [2] Quantitative analysis of hepatitis C virus in peripheral blood and liver: Replication detected only in liver
    Boisvert, J
    He, XS
    Cheung, R
    Keeffe, EB
    Wright, T
    Greenberg, HB
    [J]. JOURNAL OF INFECTIOUS DISEASES, 2001, 184 (07) : 827 - 835
  • [3] DETECTION OF VIRAL SEQUENCES OF LOW REITERATION FREQUENCY BY INSITU HYBRIDIZATION
    BRAHIC, M
    HAASE, AT
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1978, 75 (12) : 6125 - 6129
  • [4] Ultrasound-detected abdominal lymphadenopathy in chronic hepatitis C: High frequency and relationship with viremia
    Cassani, F
    Valentini, P
    Cataleta, M
    Manotti, P
    Francesconi, R
    Giostra, F
    Ballardini, G
    Lenzi, M
    Zauli, D
    Bianchi, FB
    [J]. JOURNAL OF HEPATOLOGY, 1997, 26 (03) : 479 - 483
  • [5] In situ distribution of hepatitis C virus replicative-intermediate RNA in hepatic tissue and its correlation with liver disease
    Chang, M
    Marquardt, AP
    Wood, BL
    Williams, O
    Cotler, SJ
    Taylor, SL
    Carithers, RL
    Gretch, DR
    [J]. JOURNAL OF VIROLOGY, 2000, 74 (02) : 944 - 955
  • [6] Staging the perihepatic lymph node volume in patients with primary biliary cirrhosis reflects histology.
    Dietrich, CF
    Leuschner, M
    Zeuzem, S
    Sarrazin, C
    Rees, C
    Caspary, WF
    Leuschner, U
    [J]. HEPATOLOGY, 1997, 26 (04) : 1081 - 1081
  • [7] Frequent compartmentalization of hepatitis C virus variants in circulating B cells and monocytes
    Ducoulombier, D
    Roque-Afonso, AM
    Di Liberto, G
    Penin, F
    Kara, R
    Richard, Y
    Dussaix, E
    Féray, C
    [J]. HEPATOLOGY, 2004, 39 (03) : 817 - 825
  • [8] HEPATITIS-C VIRUS-INFECTION IN PATIENTS WITH NON-HODGKINS-LYMPHOMA
    FERRI, C
    CARACCIOLO, F
    ZIGNEGO, AL
    LACIVITA, L
    MONTI, M
    LONGOMBARDO, G
    LOMBARDINI, F
    GRECO, F
    CAPOCHIANI, E
    MAZZONI, A
    MAZZARO, C
    PASERO, G
    [J]. BRITISH JOURNAL OF HAEMATOLOGY, 1994, 88 (02) : 392 - 394
  • [9] Hepatitis C virus infection in patients with overt B-cell non-Hodgkin's lymphoma in a French center
    Germanidis, G
    Haioun, C
    Pourquier, J
    Gaulard, P
    Pawlotsky, JM
    Dhumeaux, D
    Reyes, F
    [J]. BLOOD, 1999, 93 (05) : 1778 - 1779
  • [10] Effect of retreatment with interferon alone or interferon plus ribavirin on hepatitis C virus quasispecies diversification in nonresponder patients with chronic hepatitis C
    Gerotto, M
    Sullivan, DC
    Polyak, SJ
    Chemello, L
    Cavalletto, L
    Pontisso, P
    Alberti, A
    Gretch, DR
    [J]. JOURNAL OF VIROLOGY, 1999, 73 (09) : 7241 - 7247