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Tong MJ, Pan CQ, Han SB, Lu DS, Raman S, Hu K, Lim JK, Hann HW, Min AD. An expert consensus for the management of chronic hepatitis B in Asian Americans. Aliment Pharmacol Ther 2018; 47:1181-1200. [PMID: 29479728 PMCID: PMC5900913 DOI: 10.1111/apt.14577] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 10/10/2017] [Accepted: 01/27/2018] [Indexed: 12/18/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is common with major clinical consequences. In Asian Americans, the HBsAg carrier rate ranges from 2% to 16% which approximates the rates from their countries of origin. Similarly, HBV is the most important cause of cirrhosis, hepatocellular carcinoma (HCC) and liver related deaths in HBsAg positive Asians worldwide. AIM To generate recommendations for the management of Asian Americans infected with HBV. METHODS These guidelines are based on relevant data derived from medical reports on HBV from Asian countries as well as from studies in the HBsAg positive Asian Americans. The guidelines herein differ from other recommendations in the treatment of both HBeAg positive and negative chronic hepatitis B (CHB), in the approach to HCC surveillance, and in the management of HBV in pregnant women. RESULTS Asian American patients, HBeAg positive or negative, with HBV DNA levels >2000 IU/mL (>104 copies/mL) and ALT values above normal are candidates for anti-viral therapy. HBeAg negative patients with HBV DNA >2000 IU/mL and normal ALT levels but who have either serum albumin <3.5 g/dL or platelet count <130 000 mm3 , basal core promoter (BCP) mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive life-long anti-viral therapy. Indications for treatment include pregnant women with high viraemia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg positive patients with risk factors, life-long surveillance for HCC with alpha-fetoprotein (AFP) testing and abdominal ultrasound examination at 6-month intervals is required. In CHB patients receiving HCC treatments, repeat imaging with contrast CT scan or MRI at 3-month intervals is strongly recommended. These guidelines have been assigned to a Class (reflecting benefit vs. risk) and a Level (assessing strength or certainty) of evidence. CONCLUSIONS Application of the recommendations made based on a review of the relevant literature and the opinion of a panel of Asian American physicians with expertise in HBV treatment will inform physicians and improve patient outcomes.
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Affiliation(s)
- M. J. Tong
- Pfleger Liver InstituteDivision of Digestive DiseasesDavid Geffen School of Medicine at UCLALos AngelesCAUSA,Liver CenterHuntington Medical Research InstitutesPasadenaCAUSA
| | - C. Q. Pan
- Division of Gastroenterology and HepatologyNYU Langone Medical CenterNew York University School of MedicineNew YorkNYUSA
| | - S.‐H. B. Han
- Pfleger Liver InstituteDivision of Digestive DiseasesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - D. S.‐K. Lu
- Department of Radiological SciencesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - S. Raman
- Department of Radiological SciencesDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | - K.‐Q. Hu
- Division of GI/HepatologySchool of MedicineUniversity of California, IrvineOrangeCAUSA
| | - J. K. Lim
- Yale Liver Center and Section of Digestive DiseasesYale University School of MedicineNew HavenCTUSA
| | - H. W. Hann
- Liver Disease Prevention CenterDivision of Gastroenterology and HepatologySidney Kimmel Jefferson Medical College of Thomas Jefferson UniversityPhiladelphiaPAUSA
| | - A. D. Min
- Department of MedicineIcahn School of Medicine at Mount SinaiNew YorkNYUSA
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Wang T, Shen C, Chen L, Liu S, Ji Y. Association of human leukocyte antigen polymorphisms with occult hepatitis B virus infection in a Shaanxi Han population. J Gene Med 2017; 19. [PMID: 28940887 DOI: 10.1002/jgm.2987] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 08/21/2017] [Accepted: 09/13/2017] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Occult hepatitis B virus (HBV) infection (OBI) is defined as HBV DNA detection in serum or in the liver by sensitive diagnostic tests in HBV surface antigen (HBsAg) negative patients with or without serologic markers of previous HBV exposure. Because the human leukocyte antigen (HLA) system is an integral component of the immune response, we hypothesized that the highly polymorphic HLA genes were the key determinants of HBV persistence and clearance. The present study aimed to calculate the allelic frequency of HLA loci and investigate the association between HLA alleles and the outcome of OBI in Shaanxi Han population in the northwest of China. METHODS We conducted a case-control study between 107 OBI subjects and 280 healthy control individuals from blood donors of Shaanxi Blood Center. Five HLA loci, including HLA-A,-B,-C,-DRB1 and -DQB1, were selected and further genotyped using a polymerase chain reaction sequence-based typing (SBT) method. RESULTS Using the chi-squared test, we found that the allele frequencies of HLA-B*44:03 [odds ratios (OR) = 2.146, 95% confidence interval (CI) = 1.070-4.306, p = 0.028]; C*07:01 (OR = 4.693, CI = 1.822-12.086, p = 0.000); DQB1*02:02 (OR = 1.919, CI = 1.188-3.101, p = 0.007); and DRB1*07:01 (OR = 2.012, CI = 1.303-3.107, p = 0.001) were markedly higher in the OBI group compared to the healthy control group. The allele frequencies of HLA-DRB1*08:03 (OR = 0.395, CI = 0.152-1.027, p = 0.049); DRB1*15:01 (OR = 0.495, CI = 0.261-0.940, p = 0.029); and DQB1*06:02 (OR = 0.500, CI = 0.249-1.005, p = 0.048) were obviously lower in the OBI group compared to the healthy control group. These data indicated that HLA-B*44:03, C*07:01, DQB1*02:02 and DRB1*07:01 were related to OBI infection, whereas HLA-DRB1*08:03, DRB1*15:01 and DQB1*06:02 alleles were associated with HBV DNA clearance in a Shaanxi Han population. CONCLUSIONS The results of the present study suggest that host HLA gene is an important influencing factor for OBI pathogenesis.
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Affiliation(s)
- Tianju Wang
- Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China.,Blood Center of the Shaanxi Province, Xi'an, Shaanxi, People's Republic of China
| | - Chunmei Shen
- Blood Center of the Shaanxi Province, Xi'an, Shaanxi, People's Republic of China
| | - Liping Chen
- Blood Center of the Shaanxi Province, Xi'an, Shaanxi, People's Republic of China
| | - Sheng Liu
- Blood Center of the Shaanxi Province, Xi'an, Shaanxi, People's Republic of China
| | - Yanhong Ji
- Department of Immunology and Pathogenic Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
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Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H. Impact of host gene polymorphisms on susceptibility to chronic hepatitis B virus infection. INFECTION GENETICS AND EVOLUTION 2016; 44:94-105. [DOI: 10.1016/j.meegid.2016.06.043] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/21/2016] [Accepted: 06/22/2016] [Indexed: 12/15/2022]
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Bei CH, Bai H, Yu HP, Yang Y, Liang QQ, Deng YY, Tan SK, Qiu XQ. Combined effects of six cytokine gene polymorphisms and SNP-SNP interactions on hepatocellular carcinoma risk in Southern Guangxi, China. Asian Pac J Cancer Prev 2015; 15:6961-7. [PMID: 25169554 DOI: 10.7314/apjcp.2014.15.16.6961] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Cytokine gene single nucleotide polymorphisms (SNPs) are involved in the genesis and progression of hepatocellular carcinoma (HCC). We hypothesized that combined effects of cytokine gene SNPs and SNP-SNP interactions are associated with HCC risk. Six SNPs in cytokine genes (IL-2, IFN-γ, IL-1β, IL-6, and IL-10) were genotyped in a study of 720 Chinese HCC cases and 784 cancer-free controls. Although none of these SNPs individually had a significant effect on the risk of HCC, we found that the combined effects of these six SNPs may contribute to HCC risk (OR=1.821, 95% CI=1.078-3.075). This risk was pronounced among smokers, drinkers, and hepatitis B virus carriers. A SNP-SNP interaction between IL-2-330 and IFN-γ-1615 was associated with an increased HCC risk (OR=1.078, 95% CI=1.022-1.136). In conclusion, combined effects of SNPs and SNP-SNP interactions in cytokine genes may contribute to HCC risk.
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Affiliation(s)
- Chun-Hua Bei
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning, China E-mail :
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Karra VK, Gumma PK, Chowdhury SJ, Ruttala R, Polipalli SK, Chakravarti A, Kar P. IL-18 polymorphisms in hepatitis B virus related liver disease. Cytokine 2015; 73:277-82. [PMID: 25802197 DOI: 10.1016/j.cyto.2015.02.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Revised: 02/13/2015] [Accepted: 02/14/2015] [Indexed: 12/17/2022]
Abstract
Interleukine-18 (IL-18) was originally called interferon (INF-γ) inducing factor and plays a critical dual role in Th1 polarization and viral clearance. We aimed to explore whether single-nucleotide promoter polymorphisms (SNPs) are associated with the outcome of hepatitis B virus (HBV) infection. 271 HBV infected patients were recruited in this study out of these 109 were spontaneously recovered and 162 were diagnosed to be having persistent HBV infection which includes 48 chronic hepatitis, 84 liver cirrhosis, 30 HCC cases and were compared with 280 healthy controls. IL-18 promoter genotyping was performed with sequence-specific primers. The results demonstrated the significant involvement of genotype AA at position -607 in healthy controls (38.6%) when compared to cases (26.0%) (OR=0.54 (0.385-0.797)) and also associated with spontaneous clearance (37.6%) compared to persistent HBV infections (17.9%) (OR=2.76 (1.582-4.832)). Whereas, genotype CC at position -607 in cases (18.0%) when compared to healthy controls (6.7%) (OR=3.03 (1.734-5.303)) also associated with persistent HBV infections (24.1%) compared to spontaneous clearance (9.2%) (OR=0.31 (0.151-0.67)). And genotype GC at position -137 in cases (49.5%) compared to healthy controls (38.5%) (OR=1.55 (1.11-2.18)). Whereas, genotype GG at position -137 in healthy controls (56.8%) compared to cases (45.4%) (OR=0.63 (0.451-0.885)). No significant difference at position -137 was observed between spontaneous clearance and persistent HBV infections. These polymorphisms of the IL-18 gene promoter region at position -607 and -137 could be associated with different outcomes of HBV infection. The people with allele A at position -607 may be protected against HBV infection; moreover AA genotype is associated with spontaneous clearance.
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Affiliation(s)
- Vijay Kumar Karra
- PCR Hepatitis Lab, Dept. of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi 110002, India
| | - Phani Kumar Gumma
- PCR Hepatitis Lab, Dept. of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi 110002, India
| | - Soumya Jyoti Chowdhury
- PCR Hepatitis Lab, Dept. of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi 110002, India
| | - Rajesh Ruttala
- PCR Hepatitis Lab, Dept. of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi 110002, India
| | - Sunil Kumar Polipalli
- PCR Hepatitis Lab, Dept. of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi 110002, India
| | - Anita Chakravarti
- Department of Medical Microbiology, Maulana Azad Medical College, University of Delhi, New Delhi 110002, India
| | - Premashis Kar
- PCR Hepatitis Lab, Dept. of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi 110002, India.
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Hu Z, Yang J, Xiong G, Shi H, Yuan Y, Fan L, Wang Y. HLA-DPB1 Variant Effect on Hepatitis B Virus Clearance and Liver Cirrhosis Development Among Southwest Chinese Population. HEPATITIS MONTHLY 2014; 14:e19747. [PMID: 25337146 PMCID: PMC4199145 DOI: 10.5812/hepatmon.19747] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/30/2014] [Revised: 06/26/2014] [Accepted: 08/03/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Previous studies have shown that genetic variants in HLA-DP genes affect disease progression in hepatitis B virus (HBV) infection. OBJECTIVES We aimed to evaluate possible association between HLA-DPB1 rs9277534 polymorphism and different clinical complications of hepatitis B virus (HBV) infection. MATERIALS AND METHODS Snapshot assay was used to investigate the association of rs9277534 polymorphism in 342 patients with persistent HBV infection and 342 age and gender-matched HBV spontaneous clearance controls. Patients were categorized into asymptomatic HBV carriers (AsC, n = 104), chronic hepatitis B (CHB, n = 116), and liver cirrhosis (LC, n = 122) subgroups. RESULTS There was a significantly higher proportion of the rs9277534 minor allele A in HBV spontaneous clearance control than that in HBV persistent infection group (OR = 0.58, 95%CI = 0.46-0.73, P < 0.0001). Genotypic analysis showed that GA and AA genotypes were associated with HBV spontaneous clearance (GA: OR = 0.56, 95%CI = 0.40-0.79, P = 0.019; AA: OR = 0.24, 95%CI = 0.14-0.44, P < 0.0001). A significant difference was found between AsC and LC groups in the distribution of AA genotype (OR = 9.32, 95%CI = 1.293-67.14, P = 0.027). CONCLUSIONS Variant at rs9277534 could affect both the spontaneous clearance of HBV infection and progression from asymptomatic HBV carriers to HBV-related liver cirrhosis in Southwest Han Chinese population.
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Affiliation(s)
- Zhangyong Hu
- Department of Infection Diseases, First Affiliated Hospital, Chengdu Medical College, Chengdu, China
- Corresponding Author: Zhangyong Hu, Department of Infection Diseases, First Affiliated Hospital, Chengdu Medical College, Chengdu, China. Tel: +86-15388138508, Fax: +86-2883016678, E-mail:
| | - Jun Yang
- Department of Infection Diseases, First Affiliated Hospital, Chengdu Medical College, Chengdu, China
| | - Guolian Xiong
- Department of Infection Diseases, First Affiliated Hospital, Chengdu Medical College, Chengdu, China
| | - Han Shi
- Department of Infection Diseases, First Affiliated Hospital, Chengdu Medical College, Chengdu, China
| | - Yuan Yuan
- Department of Infection Diseases, First Affiliated Hospital, Chengdu Medical College, Chengdu, China
| | - Lin Fan
- Department of Infection Diseases, First Affiliated Hospital, Chengdu Medical College, Chengdu, China
| | - Yali Wang
- Department of Infection Diseases, First Affiliated Hospital, Chengdu Medical College, Chengdu, China
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Al-Qahtani A, Khalak HG, Alkuraya FS, Al-hamoudi W, Al-hamoudy W, Alswat K, Al Balwi MA, Al Abdulkareem I, Sanai FM, Abdo AA. Genome-wide association study of chronic hepatitis B virus infection reveals a novel candidate risk allele on 11q22.3. J Med Genet 2013; 50:725-32. [PMID: 24065354 DOI: 10.1136/jmedgenet-2013-101724] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) affects millions of people worldwide. While some people are able to clear the virus following the first encounter, those who develop chronic infection manifest remarkable clinical heterogeneity that ranges from asymptomatic carrier state to cirrhosis and hepatocellular carcinoma. Despite extensive studies, little is known about genetic host factors that influence the outcome of chronic HBV infection. Thus, we conducted this study to investigate the genetic risk of developing active liver disease among chronic carriers of HBV. METHODS In this study, we conducted a genome-wide association study (GWAS) on a cohort of patients with chronic HBV infection. RESULTS One particular SNP that is 16 kb upstream of Ferredoxin 1 was found to have an association with complicated chronic HBV infection (cirrhosis and hepatocellular carcinoma) that reached GWAS significance, and was successfully validated on an independent set of samples. CONCLUSIONS This first GWAS in an Arab population further demonstrates the utility of this approach in elucidating the genetic risk of HBV infection-related complications and highlights the advantage of conducting GWAS in different ethnicities to achieve that goal.
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Affiliation(s)
- Ahmed Al-Qahtani
- Department of Infection and Immunity, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
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Novel artemisinin derivatives with potential usefulness against liver/colon cancer and viral hepatitis. Bioorg Med Chem 2013; 21:4432-41. [DOI: 10.1016/j.bmc.2013.04.059] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2013] [Revised: 04/12/2013] [Accepted: 04/18/2013] [Indexed: 12/18/2022]
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Cheong JY, Shin HD, Kim YJ, Cho SW. Association of polymorphism in MicroRNA 219-1 with clearance of hepatitis B virus infection. J Med Virol 2013; 85:808-14. [DOI: 10.1002/jmv.23551] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/14/2013] [Indexed: 12/12/2022]
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YANG YAN, QIU XIAOQIANG, YU HONGPING, ZENG XIAOYUN, BEI CHUNHUA. TNF-α -863 polymorphisms and the risk of hepatocellular carcinoma. Exp Ther Med 2012; 3:513-518. [PMID: 22969921 PMCID: PMC3438725 DOI: 10.3892/etm.2011.418] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Accepted: 12/12/2011] [Indexed: 12/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a common type of highly malignant tumor. Guangxi is an area of China characterized by a high incidence of HCC. Previous epidemiological studies have found that chronic infection with hepatitis B virus (HBV) is one of the major etiological risk factors for HCC in China. With the increased understanding of the host immune response against HBV and the pathogenesis of the virus, at present, greater attention is being given to the immune response of cytokine genes, as polymorphisms may have a major impact on the course and outcome of HBV infection. In the present study, we genotyped tumor necrosis factor-α (TNF-α) rs1800629 (-308G/A), rs1800630 (-863C/A); interleukin-1B rs1143627 (-31T/C); and transforming growth factor β1 (TGF-β1) rs1800469 (-509C/T) in a hospital-based study of 772 HCC cases and 852 cancer-free controls. The distribution of the frequency of TNF-α rs1800630 sites of CC, CA, AA were 65.67, 27.46 and 6.87% in the case group, respectively, as compared with 67.02, 29.58 and 3.40% in the controls, all with a statistical significance (P<0.05). The logistic regression analysis revealed that the variant rs1800630 AA genotypes were associated with a significantly increasing risk of HCC (OR=2.058, 95% CI 1.289-3.287), compared with the wild-type rs1800630 CC. Further stratified analyses showed that after stratification for history of alcohol drinking, in a subgroup of individuals without a history of drinking, the HCC risk in the group with the TNF-α rs1800630 A allele was 1.839 times higher than that in the group with TNF-α rs1800630 C (P<0.010). These findings suggest that TNF-α rs1800630 may contribute to the risk of HCC, however, these data require further validation.
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Affiliation(s)
- YAN YANG
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning
| | - XIAO-QIANG QIU
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning
- School of Public Health, Guilin Medical University, Guilin, Guangxi, P.R. China
| | - HONG-PING YU
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning
| | - XIAO-YUN ZENG
- Department of Epidemiology, School of Public Health, Guangxi Medical University, Nanning
| | - CHUN-HUA BEI
- School of Public Health, Guilin Medical University, Guilin, Guangxi, P.R. China
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Tong MJ, Pan CQ, Hann HW, Kowdley KV, Han SHB, Min AD, Leduc TS. The management of chronic hepatitis B in Asian Americans. Dig Dis Sci 2011; 56:3143-62. [PMID: 21935699 DOI: 10.1007/s10620-011-1841-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2011] [Accepted: 07/15/2011] [Indexed: 12/14/2022]
Abstract
Hepatitis B virus (HBV) infection is common with major clinical consequences worldwide. In Asian Americans, the HBsAg carrier rate ranges from 7 to 16%; HBV is the most important cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Patients are first diagnosed at different stages of clinical disease, which is categorized by biochemical and virologic tests. Patients at risk for liver complications should be identified and offered antiviral therapy. The two antiviral agents recommended for first-line treatment of chronic hepatitis B (CHB) are entecavir and tenofovir. The primary goal of therapy is sustained suppression of viral replication to achieve clinical remission, reverse fibrosis, and prevent and reduce progression to end-stage liver disease and HCC. Asian patients with chronic hepatitis, either HBeAg-positive or -negative, with HBV DNA levels >10(4) copies/mL (>2,000 IU/mL) and alanine aminotransferase (ALT) values above normal are candidates for antiviral therapy. HBeAg-negative patients with HBV DNA >10(4) copies/mL (>2,000 IU/mL) and normal ALT levels but who have either serum albumin ≤3.5 g/dL or platelet count ≤130,000 mm(3), basal core promoter mutations, or who have first-degree relatives with HCC should be offered treatment. Patients with cirrhosis and detectable HBV DNA must receive antiviral therapy. Considerations for treatment include pregnant women with high viremia, coinfected patients, and those requiring immunosuppressive therapy. In HBsAg-positive patients with risk factors, lifelong surveillance for HCC with alpha-fetoprotein testing and abdominal ultrasound examination at 6-month intervals is required. These recommendations are based on a review of relevant literature and the opinion of a panel of Asian American physicians with expertise in hepatitis B treatment.
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Affiliation(s)
- Myron J Tong
- Pfleger Liver Institute, Division of Digestive Diseases, University of California School of Medicine, Los Angeles, CA, USA.
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Cheong JY, Cho SW, Oh B, Kimm K, Lee KM, Shin SJ, Lee JA, Park BL, Cheong HS, Shin HD, Cho BY, Kim JH. Association of interleukin-18 gene polymorphisms with hepatitis B virus clearance. Dig Dis Sci 2010; 55:1113-9. [PMID: 19466545 DOI: 10.1007/s10620-009-0819-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Accepted: 04/12/2009] [Indexed: 01/12/2023]
Abstract
The outcome of hepatitis B virus (HBV) infection can be affected by host immune factors. Interleukin-18 (IL-18) was originally discovered as an interferon-gamma-inducing factor and plays a critical role in immune response. We assessed the association between the clearance of HBV infection and single-nucleotide polymorphisms (SNPs) in the IL-18 gene. Between March 2002 and December 2004, a total of 1,050 Korean subjects were enrolled in the study and divided into two groups: (1) the HBV spontaneous recovery group (n = 320) and (2) the chronic HBV carrier group (n = 730). We analyzed SNPs at four polymorphic sites in the IL-18 gene at positions -667G>T, -148G>C, +8925C>G, and +13925A>C. We observed that the subjects bearing the IL-18 -148C allele [odds ratio (OR), 0.25; confidence interval (CI), 0.09-0.68; P = 0.01], the +8925G allele (OR, 0.36; CI, 0.15-0.88; P = 0.02), and the +13925C allele (OR, 0.25; CI, 0.13-0.82; P = 0.01) were significantly associated with HBV clearance in a recessive model. This study indicates that the -148C, +8925G, and +13925C alleles of the IL-18 gene are likely associated with HBV clearance in a Korean population.
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Affiliation(s)
- Jae Youn Cheong
- Department of Gastroenterology, Genomic Research Center for Gastroenterology, Ajou University School of Medicine, San-5 Wonchon-Dong, Youngtong-ku, Suwon, 442-721, South Korea
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Kim YJ, Lee HS. [Genetic epidemiological study on single nucleotide polymorphisms associated with hepatocellular carcinoma in patients with chronic HBV infection]. THE KOREAN JOURNAL OF HEPATOLOGY 2009; 15:7-14. [PMID: 19346781 DOI: 10.3350/kjhep.2009.15.1.7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Hepatocellular carcinoma (HCC) is associated with hepatitis B virus (HBV) as an etiologic agent in 80% of cases, and is the major cause of death among HBV carriers. Family history of HCC is a known risk factor for the development of HCC among chronically HBV infected patients; therefore, genetic factors are likely to modify the risk of HCC. However, the genetic factors that determine progression to HCC remain mostly to be recovered. It is estimated that there are millions of single nucleotide polymorphisms (SNPs) within human genome and they are likely to explain much of the genetic diversity of individuals. In this review, the natural history of HBV infection and host genetic factors related to HCC, study design and target gene selection for the detection of SNPs related to the occurrence of HCC were discussed. Also, several SNPs or haplotypes, which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection, were reviewed. Especially, recent studies in Korea, one of the HBV endemic areas, were discussed. Screening of these polymorphisms might be useful in clinical practice to stratify the lower or higher risk group for HCC and might modify the design of HCC surveillance programs in patients with chronic HBV infection, if further genetic susceptibilities are identified. The ongoing studies of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HCC, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.
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Affiliation(s)
- Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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Efferth T, Romero MR, Wolf DG, Stamminger T, Marin JJG, Marschall M. The antiviral activities of artemisinin and artesunate. Clin Infect Dis 2009; 47:804-11. [PMID: 18699744 DOI: 10.1086/591195] [Citation(s) in RCA: 327] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicine was triggered in the 1990s, by artemisinin-type sesquiterpene lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis. Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature.
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Affiliation(s)
- Thomas Efferth
- German Cancer Research Center, Pharmaceutical Biology, Im Neuenheimer Feld 280, Heidelberg, Germany.
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Cho SW, Cheong JY, Ju YS, Oh DH, Suh YJ, Lee KW. Human leukocyte antigen class II association with spontaneous recovery from hepatitis B virus infection in Koreans: analysis at the haplotype level. J Korean Med Sci 2008; 23:838-44. [PMID: 18955791 PMCID: PMC2579996 DOI: 10.3346/jkms.2008.23.5.838] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
It has been speculated that human leukocyte antigen (HLA) alleles are associated with the outcome of hepatitis B virus (HBV) infection although the data obtained from various populations have shown some inconsistencies. A total of 464 HBVinfected Korean individuals (80 spontaneously recovered [SR] and 384 chronically infected [CI]) were selected to investigate the association of HLA class II alleles with the viral clearance and persistence. Our results showed that: 1) multiple HLA class II alleles and haplotypes were associated with viral clearance (DRB1*1302, DRB1*1502, DQB1*0302, DQB1*0609, and related-haplotypes) and persistence (DRB1*0701, DQB1*0301, and related-haplotypes); 2) DRB1*1302 and DQB1* 0609 were more strongly associated with viral clearance. And the association of DQB1*0609 (pc=0.0084; OR, 7.24) with vial clearance was much stronger than previously recognized, DRB1*1302 (pc=0.0038; OR, 4.34); and 3) linkage to a specific DPB1 allele in a haplotype strengthened the association with viral clearance, although DPB1 itself was not associated with the outcome. These results indicate the existence of multiple factors controlling viral clearance in the HLA class II gene region. Further extended investigation on the genetic factors related to the outcome of HBV infection will provide valuable insights into the understanding of the mechanisms involved.
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Affiliation(s)
- Sung Won Cho
- Department of Gastroenterology, Genomic Research Center for Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Jae Youn Cheong
- Department of Gastroenterology, Genomic Research Center for Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Young Su Ju
- Department of Occupation & Environmental Medicine, College of Medicine, Hallym University, Choonchun, Korea
| | - Do Hoon Oh
- Department of Radiation Oncology, College of Medicine, Hallym University, Choonchun, Korea
| | - Young Ju Suh
- BK21 Research Division for Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | - Kyung Wha Lee
- Hallym Institution for Genome Application, College of Medicine, Hallym University, Choonchun, Korea
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16
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A fatal case of acute hepatitis B developed in a toluene abuser. Clin J Gastroenterol 2008; 1:64-68. [DOI: 10.1007/s12328-008-0009-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2008] [Accepted: 03/31/2008] [Indexed: 11/29/2022]
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17
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Nagase Y, Yotsuyanagi H, Okuse C, Yasuda K, Kato T, Koike K, Suzuki M, Nishioka K, Iino S, Itoh F. Effect of treatment with interferon alpha-2b and ribavirin in patients infected with genotype 2 hepatitis C virus. Hepatol Res 2008; 38:252-8. [PMID: 17825061 DOI: 10.1111/j.1872-034x.2007.00257.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
AIM Nearly 20% of chronic hepatitis C (CHC) patients with genotype 2 hepatitis C virus (HCV) infection are not curable, even by interferon (IFN)-ribavirin combination therapy. The aim of this study is to investigate the factors that determine the efficacy of combination therapy in patients with genotype 2 HCV infection. METHODS Fifty patients with CHC who underwent a treatment of 6 MU IFN alpha-2b with ribavirin for 24 weeks were retrospectively analyzed. RESULTS All the patients showed no serum HCV-RNA within 12 weeks after starting the therapy. Forty-one of the 50 patients (82%) achieved a sustained virological response (SVR). The age, sex, genotype (2a vs. 2b) and grade/stage of the liver by histopathology and pretreatment viral load werenot different between the sustained responders and relapsers. Univariate analysis showed that an earlier viral clearance from blood and a larger number of amino acid substitutions in the interferon sensitivity determining region (ISDR) were predictors of SVR. Multivariate analysis showed that a large number of amino acid substitutions in the ISDR was a predictor of SVR. CONCLUSION The characterization of the amino acid sequences of ISDR may be helpful for predicting a relapse after combination therapy in patients with genotype 2 HCV infection.
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Affiliation(s)
- Yoshihiko Nagase
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, St Marianna University, Kawasaki, Japan
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18
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He Q, Cheng R, Chen Z, Xiao X, Xiao Z, Li C, Li B, Zhang P, Zheng H, Feng D. Cell transformation and proteome alteration in QSG7701 cells transfected with hepatitis C virus non-structural protein 3. Acta Biochim Biophys Sin (Shanghai) 2007; 39:751-62. [PMID: 17928924 DOI: 10.1111/j.1745-7270.2007.00344.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Persistent hepatitis C virus (HCV) infection can cause liver cirrhosis and hepatocellular carcinoma. Non-structural protein 3 (NS3), an important part of HCV, has been implicated in the life cycle of the virus and interacts with host cellular proteins. In this study, we investigated the effect of NS3 protein on cell tranformation and related protein alteration in human hepatocyte QSG7701 cells. The results indicated that stable expression of the NS3 protein in QSG7701 cells induced transformed characters with reduced population doubling time, anchorage-independent growth and tumor development. Fifteen differentially-expressed proteins were separated and identified using 2-D electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Western blot analysis confirmed that the increase of phospho-p44/42 and phospho-p38 proteins was associated with transformed cells. These results supported the view that HCV NS3 protein plays a transforming role and provided some clues to elucidate the carcinogenesis mechanism of HCV-related hepatocellular carcinoma.
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Affiliation(s)
- Qiongqiong He
- Department of Pathology, Basic Medical College, Central South University, Changsha 410078, China
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19
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Kogo M, Kano A, Kiuchi Y, Mitamura K, Yoneyama K. Prognostic index for survival in patients after treatment for primary hepatocellular carcinoma. Dig Dis Sci 2007; 52:2444-51. [PMID: 17420950 DOI: 10.1007/s10620-006-9137-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2005] [Accepted: 11/07/2005] [Indexed: 01/28/2023]
Abstract
We retrospectively evaluated clinical factors affecting long-term survival after treatment for hepatocellular carcinoma (HCC) to predict the reliability of the prognosis of patients with HCC. We analyzed 157 patients who received treatment for HCC. The prognostic index (PI) was evaluated using the Cox regression model. The overall cumulative survival rates were 79.7% at 1 year, 51.1% at 3 years, and 24.9% at 5 years. The PI was calculated by the following formula, consisting of five factors: PI = 0.637 x number of tumor lesions + 0.103 x tumor diameter + 1.003 x ascites + 0.915 x portal vein tumor thrombosis - 0.006 x cholinesterase + 2.0. It was found that liver function and progression of the tumor are the most important factors for prognosis after treatment for HCC. The PI, based on five factors, will in future be an appropriate index to predict the prognosis of patients with HCC.
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Affiliation(s)
- Mari Kogo
- Department of Pathophysiology, Showa University School of Pharmaceutical Sciences, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
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20
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Narai R, Oyama T, Ogawa M, Yamaguchi T, Kinaga T, Murakami T, Isse T, Ozaki SI, Yashima Y, Okabayashi K, Ochiai H, Yarita K, Fujino A, Kawamoto T. HBV‐ and HCV‐ Infected Workers in the Japanese Workplace. J Occup Health 2007; 49:9-16. [PMID: 17314461 DOI: 10.1539/joh.49.9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Around three million Japanese are persistently infected with HBV or HCV. Though most of them work in various industries, little is known about the actual conditions in their workplaces. To clarify the workplace conditions of workers with hepatitis, three kinds of questionnaire surveys, answered by occupational health physicians and workers with hepatitis, were carried out. The rates of workers recognized as workers with hepatitis B or C by occupational health physicians were 0.82% and 0.48% of 130,092 workers, respectively. About 30% of workers with hepatitis were engaged in "hazardous work". The percentage of workers engaged in various types of hazardous work among workers with hepatitis was nearly the same as that among all Japanese workers. About 30% of occupational health physicians witnessed exacerbation of hepatitis in the workers at their workplaces, and 22% of workers with hepatitis experienced exacerbation of hepatitis. The rate of workers with hepatitis who had experienced exacerbation was not significantly different between workers with and without hazardous work. Workers with hepatitis have strong concerns about the relationship between work and exacerbation. As causes of exacerbation, occupational health physicians cited "unknown", "drinking" and "quit treatment" while workers with hepatitis answered "work-related causes", besides "unknown" and "drinking."
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Affiliation(s)
- Rie Narai
- Department of Environmental Health, University of Occupational and Environmental Health, Kitakyushu, Japan
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21
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Tang C, Chen Z, Peng G, Yang Z, Zhou L. Analysis of differential gene expression between chronic hepatitis B patients and asymptomatic hepatitis B carriers. J Gastroenterol Hepatol 2007; 22:68-73. [PMID: 17201884 DOI: 10.1111/j.1440-1746.2006.04371.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS Chronic hepatitis B virus (HBV) infection remains a serious global health problem, inducing a spectrum of diseases, including asymptomatic HBV carriage (ASC) and chronic hepatitis B (CHB). ASC and CHB represent different immunological states and their prognoses are diverse. To clarify molecular mechanisms underlying the two infection states, the differentially expressed genes between the two states were screened and identified. METHODS Subtracted complementary DNA libraries by suppression subtractive hybridization, dot blot hybridization and quantitative real-time PCR were used to identify the differentially expressed genes between subjects with CHB and those with ASC. RESULTS RNA from peripheral blood mononuclear cells from CHB and ASC subjects was subjected to suppression subtractive hybridization and resulted in isolation of subtracted complementary DNA clones. Eighty-eight randomly sampled clones were rescreened by dot blot hybridization, from which 29 clones were identified as differentially expressed genes. The differential expression of three genes was confirmed by real-time PCR in 23 subjects with CHB and 21 with ASC. CONCLUSIONS Differentially expressed genes in peripheral blood mononuclear cells between CHB and ASC have been isolated by suppression subtractive hybridization, including some new genes. Of the up-regulated genes in CHB, most are known to be responsive to inflammatory conditions. These genes might provide clues in elucidating the mechanisms of the two different HBV infection states and designing therapeutic targets for HBV infection.
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Affiliation(s)
- Cuilan Tang
- Key Laboratory of Health Ministry, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Zhejiang, China
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22
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Cheong JY, Cho SW, Chung SG, Lee JA, Yeo M, Wang HJ, Lee JE, Hahm KB, Kim JH. Genetic polymorphism of interferon-gamma, interferon-gamma receptor, and interferon regulatory factor-1 genes in patients with hepatitis B virus infection. Biochem Genet 2006; 44:246-55. [PMID: 16944293 DOI: 10.1007/s10528-006-9029-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2005] [Accepted: 12/09/2005] [Indexed: 12/13/2022]
Abstract
The natural history of hepatitis B virus (HBV) infection is probably related to host immune factors. Interferon-gamma (IFN-gamma) plays significant roles in immune defense. This study was undertaken to investigate the association between HBV infection and single nucleotide polymorphisms (SNPs) of IFN-gamma, IFN-gamma receptor (IFNGR)-1 and 2, and interferon regulatory factor (IRF)-1 genes. Between March 2002 and December 2002, 614 Korean patients were enrolled in two different groups: an HBV clearance group (n = 201), who were hepatitis B surface antigen (HBsAg) negative with antibodies to HBsAg and hepatitis B core antigen, and an HBV persistence group (n = 413), who were repeatedly HBsAg positive. We assessed polymorphisms in the IFN-gamma gene at position +874, in the IFNGR-1 gene at positions -56 and +95, in the IFNGR-2 gene at the second position of codon 64 (Gln64Arg), and in the IRF-1 gene promoter (-410, -388), and the genotype distributions of the HBV clearance and persistence groups were compared. On the basis of unconditional logistic regression analysis with adjustment for age and sex, no statistically significant association with susceptibility to persistent HBV infection was observed with the IFN-gamma, IFNGR-1 and 2, and IRF-1 gene polymorphisms under the codominant, dominant, and recessive models.
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Affiliation(s)
- Jae Youn Cheong
- Department of Gastroenterology, Genomic Research Center for Gastroenterology, Ajou University School of Medicine, San-5 Wonchon-Dong, Youngtong-ku, Suwon, South Korea
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23
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Qi S, Cao B, Jiang M, Xu C, Dai Y, Li K, Wang K, Ke Y, Ning T. Association of the -183 polymorphism in the IFN-gamma gene promoter with hepatitis B virus infection in the Chinese population. J Clin Lab Anal 2006; 19:276-81. [PMID: 16302211 PMCID: PMC6807984 DOI: 10.1002/jcla.20090] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine that plays an important role in regulating cellular immune responses. Regulation of IFN-gamma expression is considered to be strictly controlled at the transcriptional level. Two single-nucleotide polymorphisms (SNPs) within the human IFN-gamma promoter (at positions -183 and -155) are considered to influence the promoter activity by altering the acting transcription factor-1 (AP-1) binding. We sought to assess the association between the SNPs of the IFN-gamma promoter and the host susceptibility to hepatitis B virus (HBV) infection, as well as its interaction with age and gender. No polymorphism at position-155 was detected in any of the participants, but a significant difference was found in the polymorphism at position -183 between the cases and controls (G/T and T/T vs. GG; P < 0.01, odds ratio (OR) = 4.50 (95% confidence interval (CI) = 2.23-9.09). A susceptibility analysis revealed a gradually increased trend of the OR value from the young to the old group (OR = 3.03, 4.17, and 5.56). Similarly, the association of the -183 polymorphism was markedly different in females (OR = 5.71). Our data suggest that the polymorphism at position -183 of the IFN-gamma gene promoter may be associated with susceptibility to HBV infection, and age and gender factors are coordinative risk factors.
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Affiliation(s)
- Suxia Qi
- Medical College of Shandong University, Jinan City, Shandong Province, China
- Qianfo Hospital, Jinan City, Shandong Province, China
| | - Bangwei Cao
- Peking University First Hospital, Beijing, China
- Xuzhou No. 1 People's Hospital, Xuzhou City, Jiangsu Province, China
| | - Mingwei Jiang
- Xuzhou No. 1 People's Hospital, Xuzhou City, Jiangsu Province, China
| | - Changqing Xu
- Qianfo Hospital, Jinan City, Shandong Province, China
| | - Yue Dai
- Peking University First Hospital, Beijing, China
| | - Kun Li
- Qianfo Hospital, Jinan City, Shandong Province, China
| | - Kun Wang
- Medical College of Shandong University, Jinan City, Shandong Province, China
- Qianfo Hospital, Jinan City, Shandong Province, China
| | - Yang Ke
- Beijing Institute for Cancer Research, School of Oncology, Peking University, Beijing, China
| | - Tao Ning
- Beijing Institute for Cancer Research, School of Oncology, Peking University, Beijing, China
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24
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Romero MR, Efferth T, Serrano MA, Castaño B, Macias RIR, Briz O, Marin JJG. Effect of artemisinin/artesunate as inhibitors of hepatitis B virus production in an "in vitro" replicative system. Antiviral Res 2005; 68:75-83. [PMID: 16122816 DOI: 10.1016/j.antiviral.2005.07.005] [Citation(s) in RCA: 140] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2005] [Accepted: 07/04/2005] [Indexed: 12/23/2022]
Abstract
The antiviral effect against hepatitis B virus (HBV) of artemisinin, its derivative artesunate and other compounds highly purified from traditional Chinese medicine remedies, were investigated. HBV production by permanently transfected HepG2 2.2.15 cells was determined by measuring the release of surface protein (HBsAg) and HBV-DNA after drug exposure (0.01-100 microM) for 21 days. The forms of HBV-DNA released were investigated by Southern-blotting. Neutral Red retention test was used to evaluate drug-induced toxicity on host cells. The compounds were classified according to their potential interest as follows: (i) none: they had no effect on viral production (daidzein, daidzin, isonardosinon, nardofuran, nardosinon, tetrahydronardosinon and quercetin); (ii) low: they were able to markedly reduce viral production, but also induced toxicity on host cells (berberine and tannic acid) or they had no toxic effect on host cells but only had a moderate ability to reduce viral production (curcumin, baicalein, baicalin, bufalin, diallyl disulphide, glycyrrhizic acid and puerarin); (iii) high: they induced strong inhibition of viral production at concentrations at which host cell viability was not affected (artemisinin and artesunate). Moreover, artesunate in conjunction with lamivudine had synergic anti-HBV effects, which warrants further evaluation of artemisinin/artesunate as antiviral agents against HBV infection.
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Affiliation(s)
- Marta R Romero
- Department of Biochemistry and Molecular Biology, University of Salamanca, Spain
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25
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Kawamura E, Habu D, Hayashi T, Oe A, Kotani J, Ishizu H, Torii K, Kawabe J, Fukushima W, Tanaka T, Nishiguchi S, Shiomi S. Natural history of major complications in hepatitis C virus-related cirrhosis evaluated by per-rectal portal scintigraphy. World J Gastroenterol 2005; 11:3882-6. [PMID: 15991287 PMCID: PMC4504890 DOI: 10.3748/wjg.v11.i25.3882] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the correlation between the porto-systemic hypertension evaluated by portal shunt index (PSI) and life-threatening complications, including hepatocellular carcinoma (HCC), liver failure (Child-Pugh stage progression), and esophagogastric varices.
METHODS: Two hundred and twelve consecutive subjects with HCV-related cirrhosis (LC-C) underwent per-rectal portal scintigraphy. They were allocated into three groups according to their PSI: group I, PSI ≤ 10%; group II, 10%<PSI<30%; and group III, 30% ≤ PSI. Of these, selected 122 Child-Pugh stage A (Child A) subjects were included in analysis (a mean follow-up period of 5.9 ± 5.4 years, range 6 mo-21 years).
RESULTS: No significant correlation between PSI and cumulative probability of HCC incidence was observed. Cumulative probability of Child A to B progression was tended to be higher in group III than in group I, and significantly higher in group III than in group II (62% vs 34%, 62% vs 37%; P = 0.060, <0.01; respectively). Cumulative probability of varices tended to be higher in group III than in group I (31% vs 12%, P = 0.090). On multivariate analyses, significant correlation between PSI and Child A to B progression was observed, and no significant correlation between PSI and HCC incidence or varices progression was observed.
CONCLUSION: Patients with LC-C of Child A will progress to Child B rapidly after their PSI reaches 30% or higher. PSI can be used to predict occult progressive porto-systemic shunting and liver failure non-invasively. It indicates that PSI may play an important role in follow-up of the porto-systemic hypertension gradient for outpatients with LC unlike hepatic venous catheterization.
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Affiliation(s)
- Etsushi Kawamura
- Department of Nuclear Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahimachi, Abenoku, Osaka 545-8585, Japan.
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26
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Kobayashi K, Ishii M, Shiina M, Ueno Y, Kondo Y, Kanno A, Miyazaki Y, Yamamoto T, Kobayashi T, Niitsuma H, Kikumoto Y, Takizawa H, Shimosegawa T. Interferon-gamma is produced by CD8 T cells in response to HLA-A24-restricted hepatitis C virus epitopes after sustained virus loss. Clin Exp Immunol 2005; 141:81-8. [PMID: 15958073 PMCID: PMC1809409 DOI: 10.1111/j.1365-2249.2005.02018.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2005] [Indexed: 11/29/2022] Open
Abstract
Differences in cytotoxic T lymphocyte activity in hepatitis C virus infection may account for the outcome of interferon monotherapy. To investigate this hypothesis, we analysed the response of peripheral CD8(+) T cells that recognized epitopes presented by HLA-A*2402. We synthesized HLA/beta2-microglobulin/peptide complexes using two epitopes. Production of interferon-gamma by CD8(+) T cells in response to plastic-bound monomeric HLA/peptide complex was observed frequently in sustained virus responders (SVR) (n = 13) against all the peptides, NS31296-1304 (the percentage of responding patients, 61.5%) and core 129-137 (53.8%), while no interferon-gamma production was observed in non-responders (NR) (n = 13) for any of the peptides. Tetramer-staining showed the presence of CD8(+) T cells specific for all the peptides except NS31296-1304 in two SVR at the end of interferon monotherapy, although hardly any such cells were found in four NR. Specific killing was observed against peptides NS31296-1304 (3/4) and core 129-137 (1/4) in sustained responders but none in non-responders. These results suggest that the responses of cytotoxic T lymphocytes (CTLs) were induced during interferon therapy in these patients and that interferon-gamma production by CD8(+) T lymphocytes against HCV NS31296-1304 and core 129-137 are well maintained in patients with SVR compared with those with NR. These findings emphasize the importance of the CD8(+) T cell response in controlling HCV infection.
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Affiliation(s)
- K Kobayashi
- Tohoku University School of Health Sciences and Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation, Sendai, Japan.
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27
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Fujii C, Nakamoto Y, Lu P, Tsuneyama K, Popivanova BK, Kaneko S, Mukaida N. Aberrant expression of serine/threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines. Int J Cancer 2005; 114:209-18. [PMID: 15540201 DOI: 10.1002/ijc.20719] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Most cases of human hepatocellular carcinoma develop after persistent chronic infection with human hepatitis B virus or hepatitis C virus, and host responses are presumed to have major roles in this process. To recapitulate this process, we have developed the mouse model of hepatocellular carcinoma using hepatitis B virus surface antigen transgenic mice. To identify the genes associated with hepatocarcinogenesis in this model, we compared the gene expression patterns between pre-malignant lesions surrounded by hepatocellular carcinoma tissues and control liver tissues by using a fluorescent differential display analysis. Among the genes that were expressed differentially in the pre-malignant lesions, we focused on Pim-3, a member of a proto-oncogene Pim family, because its contribution to hepatocarcinogenesis remains unknown. Moreover, the unavailability of the nucleotide sequence of full-length human Pim-3 cDNA prompted us to clone it from the cDNA library constructed from a human hepatoma cell line, HepG2. The obtained 2,392 bp human Pim-3 cDNA encodes a predicted open reading frame consisting of 326 amino acids. Pim-3 mRNA was selectively expressed in human hepatoma cell lines, but not in normal liver tissues. Moreover, Pim-3 protein was detected in human hepatocellular carcinoma tissues and cell lines but not in normal hepatocytes. Furthermore, cell proliferation was attenuated and apoptosis was enhanced in human hepatoma cell lines by the ablation of Pim-3 gene with RNA interference. These observations suggest that aberrantly expressed Pim-3 can cause autonomous cell proliferation or prevent apoptosis in hepatoma cell lines.
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Affiliation(s)
- Chifumi Fujii
- Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 020-0934, Japan
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28
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Jorquera F, Monte MJ, Guerra J, Sanchez-Campos S, Merayo JA, Olcóz JL, González-Gallego J, Marin JJG. Usefulness of combined measurement of serum bile acids and ferritin as additional prognostic markers to predict failure to reach sustained response to antiviral treatment in chronic hepatitis C. J Gastroenterol Hepatol 2005; 20:547-54. [PMID: 15836702 DOI: 10.1111/j.1440-1746.2005.03725.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
AIM To investigate the relationship between serum levels of ferritin and bile acids (BA) and the response to antiviral treatment in chronic hepatitis C (HCV). METHODS A retrospective study was carried out on 35 control volunteers and 50 patients receiving interferon alpha-2b alone or plus ribavirin for 48 weeks. These were classified as sustained responders (SR) for >6 months after therapy (n = 17), non-responders (NR) (n = 27) and relapsers (RL) (n = 6). Before treatment, serum ferritin levels were determined by immunoturbidometry, 3alpha-hydroxyl-BA levels (S-3alpha-OH-BA) were assayed enzymatically and total (desulfated, deglucuronidated and deamidated) BA concentrations (STBA) by gas chromatography-mass spectrometry. RESULTS STBA were lower in controls than in patients (SR < NR + RL). The highest levels of cholic acid and chenodeoxycholic acid families were found in NR + RL. Levels of cholic acid family were similar in controls and SR, whereas those of chenodeoxycholic acid family were higher in SR than in controls. A significant correlation between STBA (but not S-3alpha-OH-BA) and ferritin was found. Apparent value to predict the absence of a sustained response was calculated by combining elevated ferritin (>300 microg/mL) and STBA or individual BA species at different cut-off values. The best degree of certainty (100% specificity) was obtained using STBA >15 microM. CONCLUSION These results recommend that larger prospective trials should be performed in chronic HCV patients to evaluate the usefulness of combined measuring of STBA and ferritin as additional prognostic markers to predict the existence of a very low probability of a sustained response to the current standard treatment, i.e. pegylated interferon in combination with ribavirin.
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Affiliation(s)
- Francisco Jorquera
- Department of Physiology and Pharmacology, University of Salamanca, Salamanca, Spain
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29
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Zhao YR, Gong L, He YL, Liu F, Lu C. Relationship between polymorphism of class II transactivator gene promoters and chronic hepatitis B. World J Gastroenterol 2005; 11:854-7. [PMID: 15682480 PMCID: PMC4250596 DOI: 10.3748/wjg.v11.i6.854] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between the polymorphism of class II transactivator (CIITA) gene promoters and chronic hepatitis B (CHB).
METHODS: Genomic DNA was prepared from peripheral blood leukocytes. Promoters I, III and IV of gene were analyzed respectively with polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) in 65 patients with CHB, 26 patients with acute hepatitis B (AHB) and 85 normal controls.
RESULTS: No abnormal migration was found in PCR-SSCP analysis of the three promoters in the three groups. Also, no sequential difference was observed at the three promoters among the CHB patients, AHB patients and normal controls.
CONCLUSION: No polymorphism in promoters I, III and IV of CIITA gene exists in CHB patients, ABH patients and normal controls, suggesting that the promoter of CIITA gene might be a conserved domain.
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Affiliation(s)
- Ying-Ren Zhao
- Department of Infectious Diseases, First Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
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Kim YJ, Lee HS. Single Nucleotide Polymorphisms Associated with Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Infection. Intervirology 2005; 48:10-5. [PMID: 15785084 DOI: 10.1159/000082089] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
It is estimated that there are millions of single nucleotide polymorphisms (SNPs) within human genome and there are likely to explain much of the genetic diversity of individuals. Hepatocellular carcinoma (HCC) is etiologically associated with hepatitis B virus (HBV) in 80% of cases, and is the dominant cause of death among HBV carriers. Among patients with chronic HBV infection, family history is a known risk factor for the development of HCC; therefore, genetic factors are likely to modify the risk of HCC. However, the genetic factors that determine progression to HCC remain mostly to be investigated. In this review, we discussed that the natural history of HBV infection and host genetic factors related to HCC, study design and target gene selection for the detection of SNPs related to the occurrence of HCC. Also, we reviewed that several SNPs or haplotypes, which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection. Screening of these polymorphisms might be useful in clinical practice to stratify the lower or higher risk group for HCC and might modify the design of HCC surveillance programs in patients with chronic HBV infection, if further genetic susceptibilities are identified.
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Affiliation(s)
- Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Kan QC, Yu ZJ, Lei YC, Yang DL, Hao LJ. Construction of the vector that harbors self-restricted system for hepatitis B virus clearance in gene therapy. Shijie Huaren Xiaohua Zazhi 2003; 11:1515-1519. [DOI: 10.11569/wcjd.v11.i10.1515] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To construct the vector that harbors self-restricted system for clearing hepatitis B virus, eliminating infected hepatic cells and inhibiting hepatitis B recurrence in gene therapy.
METHODS After amplifying hepatitis C virus (HCV) internal ribosome entry sites (IRES) by reverse-transcription PCR (RT-PCR), the products were cloned into pcDNA3. A biscistronic vector was obtained. A part of sequence in HBV anti-surface gene and part of sequence in HCV core gene were cloned into the vector before IRES site in turn and thymidine kinase (TK) was also cloned into it following the IRES site. After determination by PCR and sequencing, we acquired the vector containing HBV anti-S, HCV-C gene, HCV IRES and thymidine kinase gene, which was named the vector pcDNA3-SCITK. The vectors were separately transfected into HepG2 cells and 2.2.15 cells and all the media contained ganciclovir.
RESULTS The novel vector was transfected into 2.2.15 and hepG2 cells, the expressed protein could destroy the former, but had no effect on HepG2 cells if all the media contained ganciclovir. Apoptosis cells in the former accounted for 15 per cent of all cells by fluorescence (FACS) detection. There was obvious difference between the two types of cells (the later was only 6 per cent).
CONCLUSION The function of genes that pcDNA3-SCITK carried with self-restricted system could be ego-controlled, and it might be used as gene therapy vector for HBV clearance if taking HBV S gene as target gene and TK gene as objective gene.
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Affiliation(s)
- Quan-Cheng Kan
- Department of Clinical Immunology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zu-Jiang Yu
- Department of Infectious Disease, the First Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Yan-Chang Lei
- Department of Clinical Immunology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Dong-Liang Yang
- Department of Clinical Immunology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Lian-Jie Hao
- Department of Clinical Immunology, Tongji Medical College of Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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Fujiwara S, Sharp GB, Cologne JB, Kusumi S, Akahoshi M, Kodama K, Suzuki G, Yoshizawa H. Prevalence of hepatitis B virus infection among atomic bomb survivors. Radiat Res 2003; 159:780-6. [PMID: 12751961 DOI: 10.1667/0033-7587(2003)159[0780:pohbvi]2.0.co;2] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
The aim of this study was to determine whether the prevalence of hepatitis B virus (HBV) carriers increased with atomic bomb radiation dose, and whether radiation decreased the ability to clear HBV among the atomic bomb survivors. The study subjects were 6,121 participants in the Adult Health Study of atomic bomb survivors in Hiroshima and Nagasaki. After adjustment for age, sex, city and potential confounders, the rates of seropositivity for hepatitis B surface antigen (HBsAg), indicating current HBV infections, and anti-hepatitis B core antibody, indicating either cured or current infections, increased with radiation dose. However, no relationship was observed between radiation and anti-hepatitis B surface antibody (indicating cured infection). The proportion of persons who were unable to clear the virus, as the proportion of HBsAg-positive persons among those ever infected by HBV (positive for HBsAg or surface or core hepatitis B antibody), increased significantly with radiation dose among those receiving blood transfusions. This proportion was not related to dose among those who reported no such transfusions. The findings may suggest a lower likelihood of clearance after HBV infection among those who were more likely to have been infected with HBV as adults after atomic bomb irradiation rather than as infants or adults prior to irradiation.
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Affiliation(s)
- Saeko Fujiwara
- Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan.
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33
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Wang FS. Current status and prospects of studies on human genetic alleles associated with hepatitis B virus infection. World J Gastroenterol 2003; 9:641-4. [PMID: 12679901 PMCID: PMC4611419 DOI: 10.3748/wjg.v9.i4.641] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection can cause a broad spectrum diseases, including from asymptomatic HBV carriers or cryptic hepatitis, to acute hepatitis, chronic hepatitis, Liver cirrhosis and primary hepatocellular carcinoma. The variable pattern and clinical outcome of the infection were mainly determined by virological itself factors, host immunological factors and genetic factors as well as the experimental factors. Among the human genetic factors, major candidate or identified genes involved in the process of HBV infection fall into the following categories: (1) genes that mediate the processes of viral entry into hepatocytes, including genes involved in viral binding, fusion with cellular membrane and transportation in target cells; (2) genes that modulate or control the immune response to HBV infection; (3) genes that participate in the pathological alterations in liver tissue; (4) genes involved in the development of liver cirrhosis and hepatocellular carcinoma associated with chronic HBV infection, including genes related to mother-to-infant transmission of HBV infection; and (5) those that contribute to resistance to antiviral therapies. Most of the reports of human genes associated with HBV infection have currently focused on HLA associations. For example, some investigators reported the association of the HLA class II alleles such as DRB1*1302 or HLA-DR13 or DQA1*0501-DQB1*0301-DQB1*1102 haplotypes with acute and/or chronic hepatitis B virus infection, respectively. Several pro-inflammatory cytokines such as Th1 cytokines (including IL-2 and IFN-γ) and TNF-α have been identified to participate the process of viral clearance and host immune response to HBV. In contrast, the Th2 cytokine IL-10 serves as a potent inhibitor of Th1 effector cells in HBV diseases. The MBP polymorphisms in its encoding region were found to be involved in chronic infection. Thus, reports from various laboratories have shown some inconsistencies with regard to the effects of host genetic factors on HBV clearance and persistence. Since genetic interactions are complex, it is unlikely that a single allelic variant is responsible for HBV resistance or susceptibility. However, the collective influence of several single nucleotide polymorphisms (SNPs) or haplotype (s) may underlie the natural combinational or synergistic protection against HBV. The future study including the multi-cohort collaboration will be needed to clarify these preliminary associations and identify other potential candidate genes. The ongoing study of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HBV infection, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.
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Affiliation(s)
- Fu-Sheng Wang
- Division of Bioengineering, Beijing Institute of Infectious Diseases, 100 Xi Si-Huan-Zhong Road, Beijing 100039, China.
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Romero MR, Martinez-Diez MC, Larena MG, Macias RIR, Dominguez M, Garcia-Monzon C, Serrano MA, Marin JJG. Evidence for dual effects of DNA-reactive bile acid derivatives (Bamets) on hepatitis B virus life cycle in an in vitro replicative system. Antivir Chem Chemother 2002; 13:371-80. [PMID: 12718409 DOI: 10.1177/095632020201300605] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
A liver targeting strategy to direct antiviral drugs toward hepatitis B virus (HBV) was investigated. As model drugs we used cisplatin-bile acid derivatives (Bamets) to determine the production of virions by HBV-transfected hepatoblastoma cells (HepG2 2.2.15). Drug uptake was determined using flameless atomic absorption spectrometry to measure platinum cell contents. Cytotoxic effect was determined by formazan formation and neutral red uptake tests. The release of viral surface protein was evaluated by ELISA. The abundance of HBV-DNA in the medium was determined by quantitative real-time PCR and its structure by Southern blot analysis. The uptake of Bamets by HepG2 2.2.15 cells was higher than that of cisplatin. At concentrations lower than 10 microM, distinct Bamets have no toxic effect on host cells, whereas cisplatin dramatically reduced cell viability at concentrations higher than 1 microM. All the drugs tested inhibited the release of viral proteins to the medium, but induced a marked and progressive dose-dependent increase in the amount of viral DNA in the medium. This was mainly due to the release of short fragments of HBV-DNA in the case of cisplatin. On the contrary, Bamets induced an enhanced release of circular forms of HBV-DNA. These findings suggest the existence of a dual effect of Bamets on HBV life-cycle by enhancing the production of DNA replicative intermediates but reducing the secretion of complete virions. Altogether these characteristics recommend consideration of these compounds as a useful experimental tool in the investigation of novel liver targeted therapeutic agents based on bile acid derivatives for the treatment of HBV infections, or to carry out further studies on the HBV life cycle.
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Affiliation(s)
- Marta R Romero
- Department of Biochemistry and Molecular Biology, University of Salamanca, Spain
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Beckebaum S, Cicinnati VR, Dworacki G, Müller-Berghaus J, Stolz D, Harnaha J, Whiteside TL, Thomson AW, Lu L, Fung JJ, Bonham CA. Reduction in the circulating pDC1/pDC2 ratio and impaired function of ex vivo-generated DC1 in chronic hepatitis B infection. Clin Immunol 2002; 104:138-50. [PMID: 12165275 DOI: 10.1006/clim.2002.5245] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Dendritic cells (DCs) induce and regulate T-cell-mediated immune responses. Circulating precursor (p)DC1 and pDC2 from patients with chronic hepatitis B virus (HBV) infection were quantified by flow cytometry. To assess their function, DC1 were cultured from patients and compared to those of healthy volunteers. HBV patients exhibited a significant decrease in the proportion of freshly isolated pDC1 to pDC2. DC1 propagated from patients showed lower expression of costimulatory molecules and impaired allostimulatory capacity in comparison to controls. After exposure to proinflammatory cytokines, expression of costimulatory molecules, secretion of interleukin-12 (IL-12) and allostimulatory properties increased, but capacity for T-cell stimulation and IL-12 production remained inferior to that of control DCs. HBV-DNA was amplified by polymerase chain reaction in DC1 cultured from all patients. Viral particles were visible in DC1 by electron microscopy. These results suggest that intracellular presence of HBV impairs DC1 functional maturation and subsequent deficits in T-lymphocyte activation may contribute to viral persistence.
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Affiliation(s)
- Susanne Beckebaum
- Thomas E Starlz Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
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