Productive replication of hepatitis C virus in perihepatic lymph nodes in vivo: Implications of HCV lymphotropism
Productive replication of hepatitis C virus in perihepatic lymph nodes in vivo: Implications of HCV lymphotropism
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DOI：
10.1053/j.gastro.2005.12.039
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发表时间：
2006-04-01
期刊：
影响因子：
29.4
通讯作者：
Gretch, DR
中科院分区：
文献类型：
--
作者：
Pal, S;Sullivan, DG;Gretch, DR
背景与目的：慢性丙型肝炎的发病机制尚不清楚。这项研究检测了丙型肝炎病毒(丙型肝炎病毒)在体内感染、复制和从肝周淋巴结产生后代病毒的能力。方法：收集20例丙型肝炎合并终末期肝病患者和20例非感染阴性患者的淋巴组织标本。切片用丙型肝炎病毒核糖核酸链特异性核糖核酸探针和针对丙型肝炎病毒核心和非结构区3抗原加上B细胞(CD20)和T细胞(CD2)抗原的抗体进行探测。在选定的病例中，通过克隆频率分析和测序分析了血清、外周血单核细胞、肝脏和肝周淋巴结中的丙型肝炎病毒准种。结果：原位杂交法检测20例淋巴结标本中有17例(85%)存在丙型肝炎病毒感染，50%的病例通过检测丙型肝炎病毒复制中间产物RNA证实了丙型肝炎病毒的复制。免疫细胞化学检测到淋巴组织中存在丙型肝炎病毒核心抗原和非结构抗原。感染的细胞表型主要是CD20B细胞，尽管其他类型的细胞对丙型肝炎病毒复制标志物呈阳性。一例病例的准种分析表明，在血清中循环的变种中，68%的变种也存在于淋巴组织中，而只有40%的血清变种在肝脏中发现，这表明淋巴复制是导致丙型肝炎病毒血症的主要原因。结论：丙型肝炎病毒的淋巴亲和性为人类慢性丙型肝炎的复杂病理生物学提供了新的见解。我们首次证明了肝外丙型肝炎病毒复制对血清中循环病毒(病毒血症)的主要贡献。
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).