Hepatitis C virus (HCV) is a hepatotropic and lymphotropic RNA virus causally linked to lymphoma with a strong geographic variation. The aim of this study was to investigate the association of HCV and lymphoma in Taiwan, in which HCV is endemic.
Patients diagnosed with lymphoma from January 2004 to December 2008 were investigated for serum anti-HCV, and the infection rate was compared with that in healthy controls. Various lymphoma types were investigated for HCV infection. Immunohistochemistry was performed for HCV non-structural (NS)3 protein, and genotyping was performed by reverse transcriptase PCR.
Thirty-eight (11.0%) of 346 patients with lymphoma were positive for anti-HCV, as compared with 15 (1.8%) of 824 healthy controls (p<0.001, chi(2) test) with an age-adjusted and sex-adjusted OR of 4.57 (95% CI 2.41 to 8.68). Only nodal (five of eight cases) and splenic (two of two cases) marginal zone lymphomas (MZLs) as a group were significantly associated with HCV, as compared with mucosa-associated lymphoid tissue (MALT) lymphomas (1 of 15; p=0.002, Fisher's exact test). All 26 anti-HCV-positive cases stained for HCV-NS3 were negative. The most common genotypes were 1b (22%) and 2a (56%), with no statistical difference from 203 patients with HCV-related chronic liver disease.
The incidence of HCV infection among lymphoma patients in Taiwan was significantly higher than that for healthy controls. Furthermore, non-MALT (nodal and splenic) MZL was the only group significantly associated with HCV. A larger national study is warranted to re-confirm our findings and to elucidate if any particular HCV genotypes were related to the pathogenesis of lymphoma.
[Show abstract][Hide abstract] ABSTRACT: Hepatitis C virus (HCV) is one of the main causes of chronic liver disease. Although infection of hepatocytes is mainly responsible for manifestations of hepatitis C, the virus also invades the immune system by a yet-to-be-identified mechanism. Using human T cell lines and primary T lymphocytes as targets and patient-derived HCV as inocula, we aimed to identify how HCV gains entry into these cells. HCV replication was determined by detection of the HCV RNA replicative (negative) strand and viral proteins, while specific antibodies, knocking down gene expression and making otherwise-resistant cells prone to HCV, were employed to identify a receptor molecule determining T lymphocyte permissiveness to HCV infection. The results revealed that T cell susceptibility to HCV requires CD5, a lymphocyte-specific glycoprotein belonging to the scavenger receptor cysteine-rich family. Blocking of T cell CD5 with antibody or silencing with specific short hairpin RNA (shRNA) decreased cell susceptibility to HCV, while increasing CD5 expression by mitogen stimulation had the opposite effect. Moreover, transfection of naturally CD5-deficient HEK-293 fibroblasts with CD5 facilitated infection of these otherwise HCV-resistant cells. In contrast to T cells, hepatocytes do not express CD5. The data revealed that CD5 is a molecule important for HCV entry into human T lymphocytes. This finding provides direct insight into the mechanism of HCV lymphotropism and defines a target for potential interventions against HCV propagating in this extrahepatic compartment.
Journal of Virology 01/2012; 86(7):3723-35. DOI:10.1128/JVI.06956-11 · 4.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The precise molecular pathogenesis of splenic marginal zone lymphoma (SMZL) is still unknown. Clinical and epidemiological data suggest that chronic hepatitis C virus (HCV) infection may have an etiological role in a subset of cases.We performed a large-scale microRNA (miRNA) expression profiling analysis of 381 miRNAs by quantitative reverse transcription PCR (Q-RT-PCR) of 26 microdissected splenic tissue samples (7 HCV(+) SMZL; 8 HCV(-) SMZL and 11 non-neoplastic splenic controls). Single assay Q-RT-PCR and miRNA in situ hybridization (miRNA-ISH) were used to confirm the results in an independent cohort. Unsupervised hierarchical clustering of miRNA expression profiles demonstrated a distinct signature of SMZL compared with the normal splenic marginal zone. Supervised analysis revealed differentially expressed miRNAs, including miRNAs with previously recognized tumor suppressive or oncogenic potential. Five miRNAs were found significantly overexpressed in SMZL, including miR-21, miR-155 and miR-146a, whereas seven miRNAs showed significantly reduced expression, including miR-139, miR-345, miR-125a and miR-126. Furthermore, we identified miR-26b, a miRNA known to have tumor suppressive properties, as significantly downregulated in SMZL arising in HCV-positive patients (P=0.0016). In conclusion, there is a characteristic dysregulation of miRNA expression in SMZL with a possible implication in its molecular tumorigenesis.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2012; 26(7):1654-62. DOI:10.1038/leu.2012.29 · 10.43 Impact Factor
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