HDAg及其与HDV RNA复制有关的研究

本文主要阐述HDAg形成的分子机制、HDAg的两种形式对HDV RNA复制的作用及对HDV RNA复制调控的研究进展。     

Prevalence and significance of intrahepatic hepatitis delta virus antigen expression in HBeAg-negative patients with chronic type-B hepatitis in Taiwan

A consecutive series of 97 HB_eAg-negative patients with chronic type-B hepatitis, who were not drug addicts or hemophiliacs, were examined for the prevalence of intrahepatic expression of hepatitis delta virus (HDV) antigen (HDAg) by direct immunofluorescence. The clinical and histological features were compared between those with and without intrahepatic HDAg expression. Intrahepatic HDAg expression was detected in 15 (15.5%) of the 97 patients. All of the 15 were males between 18 and 71 years of age. Each had elevated SGPT levels, with 46.8% being greater than 10 times normal and 73.4% greater than five times normal. Histological study revealed chronic lobular hepatitis in nine and chronic active hepatitis in six, including two with cirrhosis. Compared to the 82 patients without intrahepatic HDAg expression, no difference in the age (34.1±14.3 vs 36.7±10.8) and sex (150 vs 7210) distribution was evident, but greater biochemical and histological activity was present in HDV-positive patients.This work was supported by Chang Gung Medical Research grant MRP 197 and a grant from the Prosperous Foundation, Taipei.     

Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level

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AAV-HDV: An Attractive Platform for the In Vivo Study of HDV Biology and the Mechanism of Disease Pathogenesis †

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis, but little is known about the molecular mechanisms involved. We have recently developed an HDV mouse model based on the delivery of HDV replication-competent genomes using adeno-associated vectors (AAV), which developed a liver pathology very similar to the human disease and allowed us to perform mechanistic studies. We have generated different AAV-HDV mutants to eliminate the expression of HDV antigens (HDAgs), and we have characterized them both in vitro and in vivo. We confirmed that S-HDAg is essential for HDV replication and cannot be replaced by L-HDAg or host cellular proteins, and that L-HDAg is essential to produce the HDV infectious particle and inhibits its replication. We have also found that lack of L-HDAg resulted in the increase of S-HDAg expression levels and the exacerbation of liver damage, which was associated with an increment in liver inflammation but did not require T cells. Interestingly, early expression of L-HDAg significantly ameliorated the liver damage induced by the mutant expressing only S-HDAg. In summary, the use of AAV-HDV represents a very attractive platform to interrogate in vivo the role of viral components in the HDV life cycle and to better understand the mechanism of HDV-induced liver pathology.     

Genotypes and phylogenetic characterization of hepatitis B and delta viruses in Egypt

Hepatitis B virus (HBV) and hepatitis D virus (HDV) sequences among HBV carriers from Egypt have not been evaluated sufficiently. The genotypes of HBV isolated from 105 serum samples from Egyptian carriers were determined. Four complete genomes and 11 entire preS1/S2/S genes were sequenced and evaluated. All serum samples were classified into HBV genotype D using serologic and genetic methods. The length of four complete nucleotide sequences was 3,182 bp. In all 15 samples, the common 33 nucleotides (11 amino acids) deletions in the preS1 region specific for HBV genotype D were observed. In the phylogenetic analysis based on the complete nucleotide sequences, all samples were clustered with the HBV isolates reported from previously Western and Mediterranean countries with nucleotide homology ranging from 96.0-98.0%. Of 75 HBsAg positive samples, anti-HDV was found in 15 (20%), and HDV RNA was detected in 9 of 15 (60%). The proportion of the patients with liver disease was higher in HBV carriers of anti-HDV positive with HDV RNA than in HBV carriers of anti-HDV positive without HDV RNA (P < 0.05). In the phylogenetic analysis based on the sequences in nucleotide position 853-1267 of HDV, nine samples were classified into HDV genotype I with the nucleotide homology ranging from 88.3-92.1% (mean; 90.5%) and clustered with HDV strains reported previously from Ethiopia, Somalia, Egypt, and Lebanon. These results indicate that HBV genotype D and HDV genotype I are most prevalent in Egypt, and HDV co-infection in HBV carriers is related to severity of liver disease.     

Comparative analysis of serological markers of chronic delta infection: HDV-RNA, serum HDAg and anti-HD IgM

To study the concordance, sensitivity and specificity of HDV-RNA determination by molecular hybridization, serum HDAg by immunoblot and anti-HD IgM by commercial enzyme immunoassay as compared to intrahepatic HDAg detection by an immunoperoxidase method, a statistical analysis was applied to the results of serum sample and liver biopsy determinations in 50 patients with chronic delta hepatitis (38 positive to tissue HDAg and 12 negative).Of the 38 patients with hepatic HDAg, HDV-RNA was found in 31 (82%), serum HDAg by immunoblot in 27 (71%) and anti-HD IgM in 33 (87%). Among the 12 patients without hepatic HDAg, one was found with serum HDAg using the immunoblot technique, two (17%) had HDV-RNA, and 7 (58%) had anti-HD IgM. Serum HDAg determination by immunoblot was the most specific test, followed by HDV-RNA analysis. The least specific was the anti-HD IgM technique. The anti-HD IgM test was the most sensitive, followed by HDV-RNA and serum HDAg. The concordance with intrahepatic HDAg detection was highest for HDV-RNA determination, followed by HDAg in serum. The least degree of concordance was found with anti-HD IgM determination. These results suggest that the determination of HDV-RNA by the hybridization method can be of great value for the diagnosis and monitoring of chronic delta hepatitis.     

慢性乙肝患者HDV二重感染的定位研究

采用免疫荧光与免疫酶标方法对145饲慢性肝病患者肝内丁型肝炎抗原(HDAg)定位研究。在95例HBsAg阳性慢性肝病患者中发现6例HDAg阳性(6.3％),在79例HBsAg阳性慢性肝炎中检出率为7.6％。在HBsAg阳性肝硬化、慢性活动性肝炎和慢性迁延性肝炎中,HD-Ag检出率分别为14.3％、7.1％和5.9％。结果提示,我国一部分慢性乙肝患者也是HDV携带者。这是我国肝炎防治研究中的新课题。     

肝内HDAg阳性的慢性丁型肝炎的临床病理探讨

对肝内HDAg阳性的慢性丁型肝炎患者临床资料分析表明:若慢性乙肝患者突然出现急性肝炎样表现或反复发作,并且病情进行性发展为肝硬化者,应考虑合并丁型肝炎病毒感染的可能;患者肝内HDAg持续阳性,常预后不良。免疫病理资料提示:HDAg阳性肝细胞周围常不能见到炎性细胞,尤其是淋巴细胞的包绕;部分含HDAg肝细胞,特别胞浆型的阳性细胞可呈气球样变性或萎缩或坏死,似支持HDV具有直接致病作用的观点。