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PubMed2000

Antiviral therapy to prevent and treat hepatitis B virus infection in hepatic allografts.

Hepatitis B infection of a liver allograft can have serious consequences including a negative influence on the probability of survival. Therefore, there is a need for very effective antiviral therapy for transplant recipients. In this article the early experience with nucleoside analogue antiviral agents, both to prevent and to treat hepatitis B in liver allografts, is reviewed. There are several important characteristics of these agents that are already apparent. Ganciclovir and famciclovir have limited efficacy in treating infections when they are used alone. These compounds might be beneficial if used after resistance develops to other drugs or when used in combination with other agents. Lamivudine is effective for about two-thirds of patients in preventing and treating hepatitis B infection in allografts. Hepatitis B immune globulin (HBIg) is known to increase the efficacy of lamivudine in preventing infection. A large study to further characterize this combination therapy is being organized. Resistance to famciclovir and lamivudine can occur if they are used alone for a long time. In order to lower the incidence of drug resistance, it may be necessary to utilize combinations of nucleoside analogues.

2-Aminopurine↗

PubMedDate not supplied

Natural history of hepatitis C virus infection.

Hepatitis C virus (HCV) is a common transmissible agent responsible for a significant proportion of chronic liver disease, cirrhosis and hepatocellular carcinoma worldwide. The natural history of acute HCV infection is characterized by a high rate of progression to persistent infection. The resulting chronic liver disease is dependent upon a delicate balance of host, viral and environmental factors which may significantly influence its clinical outcome.

Carcinoma, Hepatocellular↗

PubMed2001

[Role of neutralizing antibodies and cellular immunity in hepatitis C virus infection].

Hepatitis C virus (HCV) is responsible for the development of a chronic carrier state that can lead to the induction of cirrhosis and liver cancer. These clinical manifestations are believed to be the direct consequence of the viral persistence and the incapacity of the host to develop vigorous and sustained immune responses. Still contradictory data suggest the existence of neutralizing antibodies specifically directed at the second glycoprotein (E2). These antibodies may nonetheless play only a minor role in the control of infection. In contrast, it is now generally recognized that cellular-mediated immune responses, CD4+ and CD8+ mediated, if in place early enough, of a vigorous and polyclonal nature as well as long-lasting, appear by themselves competent enough to control an infection. One of the mechanisms possibly responsible for the establishment and persistence of a chronic infection could be the alteration of the ability of antigen-presenting cells (dendritic cells) to stimulate a T cell response. Such alteration could be the result of a direct infection of these cells by HCV.

CD4-Positive T-Lymphocytes↗

PubMed2003

Lack of epidemiological evidence for a role of resolved hepatitis B virus infection in hepatocarcinogenesis in patients infected with hepatitis C virus in Japan.

OBJECTIVE: The role of resolved hepatitis B virus (HBV) infection in promoting hepatocellular carcinoma (HCC) in patients infected with hepatitis C virus (HCV) in Japan was evaluated by epidemiological surveys. METHODS: Antibody to hepatitis B core (anti-HBc) was determined in age-matched blood donors, and the frequency was compared with that in patients with HCV-associated HCC in Japan. RESULTS: Anti-HBc was detected significantly more frequently in the blood donors with than without antibody to HCV (anti-HCV; 76/135 or 56.3% vs. 65/255 or 25.5%, p < 0.001). In the patients with HCV-associated HCC, anti-HBc was detected in 109 of 202 (54.0%), which was comparable to the frequency in anti-HCV-positive blood donors (56.3%). Among the blood donors with anti-HCV, the prevalence of anti-HBc was no different between those with and without HCV RNA in serum (40/77 or 51.9% vs. 36/58 or 62.1%). CONCLUSIONS: The individuals of an age with high cancer frequency (>or=40 years) in Japan would have been exposed to HBV frequently (>50%), whether or not they have developed HCV-associated HCC. Despite repeated assertions in the literature, no epidemiological evidence was obtained for a role of past HBV infection in hepatocarcinogenesis in patients infected with HCV in Japan.

Aged↗

PubMed1994

"Inapparent" hepatitis B virus infection and hepatitis C virus replication in alcoholic subjects with and without liver disease.

We evaluated hepatitis B virus DNA and hepatitis C virus RNA in sera from 110 HBsAg and IgM HBc antibody-negative heavy drinkers (50 cirrhosis, 13 chronic active hepatitis, 25 fatty liver with or without mild to moderate fibrosis, alcoholic hepatitis or both and 22 healthy alcoholic subjects) with polymerase chain reaction. Results of hepatitis C virus polymerase chain reaction were compared with those obtained with two tests (second generation recombinant immunoblot assay and enzyme-linked immunosorbent assay) used to detect hepatitis C virus antibodies. Hepatitis B virus DNA was found in three (2.7%) patients. Hepatitis C virus RNA was detected in 29 (29.8%) of the 97 subjects whose sera were well preserved for RNA extraction (42.5% cirrhosis, 83.3% chronic active hepatitis, 8% fatty liver and 0% healthy alcoholic subjects). Results obtained with second-generation recombinant immunoblot assay and enzyme-linked immunosorbent assay had a high degree of agreement with polymerase chain reaction as expected, the kappa indexes being 0.76 and 0.61, respectively. Nevertheless, five hepatitis C virus RNA-positive patients had negative recombinant immunoblot assay results, whereas all hepatitis C virus RNA-positive patients had positive or borderline enzyme-linked immunosorbent assay results. We conclude that, in Italian HBsAg-negative alcoholic patients, "inapparent" hepatitis B virus infection is rare. On the contrary, hepatitis C virus infection, as detected on hepatitis C virus polymerase chain reaction, is quite frequent, especially in patients who have cirrhosis and chronic active hepatitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2000

HLA association with hepatitis C virus infection.

Hepatitis is one of the most important infectious diseases in Thailand. The knowledge of host factors that influence the course of the disease is still limited. In this study, the HLA class I and class II phenotypes were analyzed in the 2 groups of HCV-infected Thai populations. The first group included 43 individuals with transient HCV infection (HCV antibody positive, HCV RNA PCR negative), and the second included 57 individuals with persistent chronic HCV infection (HCV antibody positive, PCR positive). HLA class I typing was performed by 2-stage microlymphocytotoxicity test, and HLA class II typing, by PCR-SSO. No significant difference in the frequencies of HLA-A and -B antigens was observed between the 2 groups of HCV-infected individuals. The frequency of DRB1*0301 and DQB1*0201 was significantly higher in the persistent-infection group than in the transient-infection group (Pc = 0.03, Pc = 0.04, respectively). In addition, DRB1*0701 and DQA1*0201 were significantly decreased in all the HCV-infected patients compared with levels in the normal controls (Pc = 0.003, Pc = 0.001, respectively). This study demonstrated that DRB1*0301 and DQB1*0201 are associated with persistent HCV infection, whereas DRB1*0701 and DQA*0201 are associated with protection against HCV infection.

Disease Susceptibility↗

PubMed2002

Hydrodynamic injection of viral DNA: a mouse model of acute hepatitis B virus infection.

Hepatitis B virus (HBV) is a prototype for liver-specific pathogens in which the failure of the immune system to mount an effective response leads to chronic infection. Our understanding of the immune response to HBV is incomplete, largely due to the narrow host restriction of this pathogen and the limitations of existing experimental models. We have developed a murine model for studying human HBV replication, immunogenicity, and control. After transfection of hepatocytes in vivo with a replication-competent, over-length, linear HBV genome, viral antigens and replicative intermediates were synthesized and virus was secreted into the blood. Viral antigens disappeared from the blood as early as 7 days after transfection, coincident with the appearance of antiviral antibodies. HBV transcripts and replicative intermediates disappeared from the liver by day 15, after the appearance of antiviral CD8 + T cells. In contrast, the virus persisted for at least 81 days after transfection of NOD/Scid mice, which lack functional T cells, B cells, and natural killer (NK) cells. Thus, the outcome of hydrodynamic transfection of HBV depends on the host immune response, as it is during a natural infection. The methods we describe will allow the examination of viral dynamics in a tightly controlled in vivo system, the application of mutagenesis methods to the study of the HBV life cycle in vivo, and the dissection of the immune response to HBV using genetically modified mice whose immunoregulatory and immune effector functions have been deleted or overexpressed. In addition, this methodology represents a prototype for the study of other known and to-be-discovered liver-specific pathogens.

Animals↗

PubMed1993

Routine laboratory diagnosis of hepatitis C virus infection.

Hepatitis C virus (HCV) is the major cause of parenterally transmitted non-A, non-B hepatitis. The analysis of the genomic sequence of HCV has facilitated the development of a number of diagnostic assays for testing circulating antibodies in serum from patients with HCV infection. Besides the first-generation ELISA and RIBA, which employed the C100-3 non-structural polypeptide, second-generation tests employing both structural and non-structural polypeptides are being rapidly introduced. Several coded panels were employed in a comparative study of HCV-SP ELISA (utilizing a new synthetic peptide whose sequence was derived from the structural region) along with first- and second-generation tests. On the basis of the results, evidently antigens corresponding to the structural components of the virus are more sensitive and specific for the early detection of HCV antibodies than tests using non-structural epitopes. Additionally epitopes of the structural region elicit a very strong antibody response in laboratory animals. An example of one such application is the detection of HCV specific antigens in semen from patients diagnosed with non-A, non-B (NANB) hepatitis. Semen samples from 9 patients clinically diagnosed as having NANB hepatitis were tested by an ELISA using antibodies against HCV-specific structural antigens. The semen from all 9 patients had HCV-specific structural antigens in comparison to semen from 5 healthy donors. Semen from 5 of the 9 patients had significant levels of the HCV-specific antigen. This approach to detecting HCV antigens could, if rigorously tested, evolve into promising new assays for detecting HCV.

Amino Acid Sequence↗

PubMed1994

Southern hybridisation analysis of HBV DNA in peripheral blood leucocytes and of different cell types: changes during the natural history and with interferon-alpha therapy in patients with hepatitis B virus infection.

Hepatitis B virus (HBV) DNA was evaluated in peripheral blood mononuclear cells (PBMC) from 50 individuals utilising Southern hybridisation analysis. HBV DNA sequences were detected in PBMC from 16/29 (55 percent) of chronic hepatitis B virus (HBV) carriers with serum HBeAg and HBV DNA, compared with 1/8 (13%) of carriers with anti-HBe and HBV DNA negative (P = NS). Two of 7 patients with previous HBV infection and chronic liver disease had detectable HBV DNA in PBMC. Of the 19 patients with HBV DNA in PBMC, 18 had high molecular weight species. In addition, five of these had free, monomeric HBV DNA and six patients had low molecular weight bands. For nine of the above patients, total peripheral blood leucocytes were separated into PBMC and polymorphonuclear cells. Four had HBV DNA in PBMC only, two only in polymorphonuclear cells and three in both types of cell. Eleven patients with chronic HBV infection were studied at monthly intervals for 6 months. Six were untreated and five received IFN-alpha. Three patients who responded to IFN-alpha had HBV DNA present in PBMC before therapy, and two became negative. Two of 3 untreated patients had intermittent HBV DNA in PBMC and the other remained persistently negative. Of the patients positive on more than one occasion, the pattern of HBV DNA was similar. Peripheral blood leucocytes often contain multimers of free HBV DNA, more commonly in patients with serum HBeAg and HBV DNA and may occur even in the absence of serum HBsAg. These findings have implications for recurrence of disease after hepatic transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Blotting, Southern↗

PubMed1994

Prevalence of hepatitis C virus with different genotypes determined by a group-specific antibody assay in Japanese patients with chronic liver diseases due to hepatitis C virus infection.

Hepatitis C virus (HCV) genotypes (groups I and II) were determined by a newly developed C14 assay in which antibodies against group-specific recombinant proteins of the NS4 region were measured by ELISA (enzyme-linked immunosorbent assay). The genotypes determined by the C14 assay were compared to those determined by a polymerase chain reaction (PCR) in 50 patients. The HCV genotypes determined by both methods were consistent in 78% of the patients. The results of the assays were not contradictory in any patient. The sensitivity of the C14 assay was as high as over 90%. Frequency of HCV genotypes was studied in 300 patients with chronic liver diseases type C by using the C14 assay. The prevalence of groups I and that of II in patients with chronic hepatitis were 73% and 21%, the correspondence figures in those with liver cirrhosis 80% and 13%, and in those with hepatocellular carcinoma 81% and 13%, respectively. The clinical characteristics were similar between the patients with group I and II HCV infections in each disease category. In conclusion, the C14 assay is useful for epidemiological studies of HCV genotypes, and group I is a major HCV genotype of chronic liver diseases type C in Japan.

Adult↗

PubMed2005

T cell response in hepatitis C virus infection.

Hepatitis C virus (HCV) is a hepatotropic RNA virus that causes acute and chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. It is widely accepted that cellular immune responses play an important role in viral clearance and disease pathogenesis. However, HCV often evades effective immune recognition and has a propensity to persist in the majority of acutely infected individuals (ca. 80%). The immunological and virological basis for the inefficiency of the cellular immune response to clear or control the virus is not known. Recent studies, however, have provided new insights into the mechanisms of viral clearance and persistence that will be discussed in detail.

Animals↗

PubMed2005

Strain-specific T-cell suppression and protective immunity in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) frequently persists with an apparently ineffective antiviral T-cell response. We hypothesized that some patients may be exposed to multiple HCV subtypes and that strain-specific T cells could contribute to the viral dynamics in this setting. To test this hypothesis, CD4 T-cell responses to three genotype 1a-derived HCV antigens and HCV antibody serotype were examined in chronically HCV infected (genotypes 1a, 1b, 2, 3, and 4) and spontaneously HCV recovered subjects. Consistent with multiple HCV exposure, 63% of patients infected with genotypes 2 to 4 (genotypes 2-4) and 36% of those infected with genotype 1b displayed CD4 T-cell responses to 1a-derived HCV antigens, while 29% of genotype 2-4-infected patients showed serotype responses to genotype 1. Detection of 1a-specific T cells in patients without active 1a infection suggested prior self-limited 1a infection with T-cell-mediated protection from 1a but not from non-1a viruses. Remarkably, CD4 T-cell responses to 1a-derived HCV antigens were weakest in patients with homologous 1a infection and greater in non-1a-infected patients: proportions of patients responding were 19% (1a), 36% (1b), and 63% (2-4) (P = 0.0006). Increased 1a-specific CD4 T-cell responsiveness in non-1a-infected patients was not due to increased immunogenicity or cross-reactivity of non-1a viruses but directly related to sequence divergence. We conclude that the T-cell response to the circulating virus is either suppressed or not induced in a strain-specific manner in chronically HCV infected patients and that, despite their ability to clear one HCV strain, patients may be reinfected with a heterologous strain that can then persist. These findings provide new insights into host-virus interactions in HCV infection that have implications for vaccine development.

Case-Control Studies↗

PubMed1994

Hepatic expression of interferon-alpha in chronic hepatitis B virus infection.

Hepatic expression of interferon-alpha (IFN-alpha) was examined by immunohistochemistry in 90 Chinese patients (M/F 67:23, age: 14-69) with a spectrum of hepatitis B virus (HBV)-related chronic liver diseases. Immunoreactive IFN-alpha was detected in sinusoidal cells in 79 patients (88%) and in mononuclear cells in 59 patients (65.6%). Patients with active liver diseases (chronic active hepatitis, active cirrhosis, N = 55) had a higher level of IFN-alpha expression compared to patients with inactive histology (N = 35; sinusoidal cells, P < 0.01; mononuclear cells, P < 0.01). Cytoplasmic HBsAg, nuclear HBcAg, and cytoplasmic HBcAg were detected in 79 (88%), 42 (47%), and 23 (27%) patients respectively. Expression of IFN-alpha in mononuclear cells correlated with the expression of cytoplasmic HBcAg (P < 0.05) but not with nuclear HBcAg or cytoplasmic HBsAg. When the patients were divided into four different phases according to the natural history of chronic HBV infection, patients in the active liver disease phase had higher IFN-alpha expression compared to the immunotolerant and late phase patients (P < 0.01). Using double immunohistochemical staining, both IFN-alpha and cytoplasmic HBcAg were frequently detected near inflammatory infiltrates but no correlation existed between the hepatic expression of HBsAg and IFN-alpha. These data indicate that IFN-alpha is expressed in the liver in HBV-related active liver diseases and that the reported suboptimal production of IFN-alpha by PBMC in HBV-related chronic active liver diseases may be due to a redistribution of the IFN-alpha-producing mononuclear cells into the liver, the site of inflammation.

Adolescent↗

PubMedDate not supplied

[Influence of HIV infection on hepatitis B virus infection in homosexual patients].

Clinical expression and outcome of hepatis B virus infections associated with human immunodeficiency virus infection (without AIDS) were studied in 17 homosexuals during 23 months. In an attempt to distinguish the respective impacts of homosexuality from that of human immuno-deficiency virus, patient were compared with a population of homosexual males infected by hepatitis B virus alone. The ratio of biochemical evidence of liver cell necrosis (ALAT)/viral replication (DNAp) was significatively decreased (p less than 0.01), despite evidence of severe histological damage in some cases. Two-thirds of patients with HBV replication tolerated HBV infection at the end of follow-up. This tolerance was significatively more common than in homosexuals infected by HBV alone (p less than 0.01), and did not appear to be related to decreased T4 cell count but seemed to correlate with the existence of the AIDS related complex.

Adult↗

PubMed2026

Differential Proteomic Profiling of Responders and Non-responders to Direct-Acting Antivirals Treatment in Chronic Hepatitis C Virus Infection.

Hepatitis C Virus (HCV), particularly genotype 3 (GT-3), is highly prevalent in India and is associated with faster progression to cirrhosis, hepatocellular carcinoma, and higher treatment failure rates. Although Direct-Acting Antivirals (DAAs) have revolutionized HCV therapy, 5-10% of patients fail to achieve sustained virological response (SVR). This proteomic study aimed to identify changes in the proteomic profile before and after treatment of both responders and non-responders to HCV treatment. Paired plasma samples from HCV GT-3 infected patients were collected before and 12 weeks after initiating DAAs treatment, along with healthy controls. Quantitative proteomic analysis was performed on the paired samples. Differentially expressed proteins (DEPs) were identified and subjected to functional analysis including gene set enrichment analysis (GSEA) and protein-protein interaction (PPI) network analysis. GSEA revealed enrichment in extracellular matrix organization and innate immune pathways. Expression patterns of candidate proteins selected based on fold change and false discovery rate (FDR) criteria were further evaluated in an independent cohort. Western blot confirmed key expression trends of candidate proteins. Proteins linked to extracellular matrix remodeling and angiogenesis showed differential expression patterns. Successful validation of these candidate proteins in large independent cohorts holds potential to predict therapeutic outcomes.

Humans↗

PubMed2006

Diverse CD81 proteins support hepatitis C virus infection.

Hepatitis C virus (HCV) entry is dependent on CD81. To investigate whether the CD81 sequence is a determinant of HCV host range, we expressed a panel of diverse CD81 proteins and tested their ability to interact with HCV. CD81 large extracellular loop (LEL) sequences were expressed as recombinant proteins; the human and, to a low level, the African green monkey sequences bound soluble HCV E2 (sE2) and inhibited infection by retrovirus pseudotype particles bearing HCV glycoproteins (HCVpp). In contrast, mouse or rat CD81 proteins failed to bind sE2 or to inhibit HCVpp infection. However, CD81 proteins from all species, when expressed in HepG2 cells, conferred susceptibility to infection by HCVpp and cell culture-grown HCV to various levels, with the rat sequence being the least efficient. Recombinant human CD81 LEL inhibited HCVpp infectivity only if present during the virus-cell incubation, consistent with a role for CD81 after virus attachment. Amino acid changes that abrogate sE2 binding (I182F, N184Y, and F186S, alone or in combination) were introduced into human CD81. All three amino acid changes in human CD81 resulted in a molecule that still supported HCVpp infection, albeit with reduced efficiency. In summary, there is a remarkable plasticity in the range of CD81 sequences that can support HCV entry, suggesting that CD81 polymorphism may contribute to, but alone does not define, the HCV susceptibility of a species. In addition, the capacity to support viral entry is only partially reflected by assays measuring sE2 interaction with recombinant or full-length CD81 proteins.

Amino Acid Sequence↗

PubMed2007

Scavenger receptor BI and BII expression levels modulate hepatitis C virus infectivity.

Hepatitis C virus (HCV) enters cells via a pH- and clathrin-dependent endocytic pathway. Scavenger receptor BI (SR-BI) and CD81 are important entry factors for HCV internalization into target cells. The SR-BI gene gives rise to at least two mRNA splice variants, SR-BI and SR-BII, which differ in their C termini. SR-BI internalization remains poorly understood, but SR-BII is reported to endocytose via a clathrin-dependent pathway, making it an attractive target for HCV internalization. We demonstrate that HCV soluble E2 can interact with human SR-BI and SR-BII. Increased expression of SR-BI and SR-BII in the Huh-7.5 hepatoma cell line enhanced HCV strain J6/JFH and JFH infectivity, suggesting that endogenous levels of these receptors limit infection. Elevated expression of SR-BI, but not SR-BII, increased the rate of J6/JFH infection, which may reflect altered intracellular trafficking of the splice variants. In human plasma, HCV particles have been reported to be complexed with lipoproteins, suggesting an indirect interaction of the virus with SR-BI and other lipoprotein receptors. Plasma from J6/JFH-infected uPA-SCID mice transplanted with human hepatocytes demonstrates an increased infectivity for SR-BI/II-overexpressing Huh-7.5 cells. Plasma-derived J6/JFH infectivity was inhibited by an anti-E2 monoclonal antibody, suggesting that plasma virus interaction with SR-BI was glycoprotein dependent. Finally, anti-SR-BI antibodies inhibited the infectivity of cell culture- and plasma-derived J6/JFH, suggesting a critical role for SR-BI/II in HCV infection.

Animals↗

PubMed2001

Recent advances in prevention and treatment of hepatitis C virus infections.

Hepatitis C virus (HCV) is the leading cause of chronic hepatitis in humans. As members of the flavivirus family, HCVs are a group of small single-stranded, positive-sense RNA viruses. Upon translation of the genome, a polyprotein precursor is synthesized and further processed by both cellular and viral proteases to generate functional viral proteins. Treatment options are currently limited to the administration of alpha-interferon alone or in combination with ribavirin. Unfortunately, these approaches are characterized by relatively poor efficacy and an unfavorable side-effect profile. Therefore, intensive effort is directed at the discovery of novel molecules to treat this disease. These new approaches include the development of prophylactic and therapeutic vaccines, the identification of interferons with improved pharmacokinetic characteristics, and the discovery of novel drugs designed to inhibit the function of three major viral proteins: protease, helicase and polymerase. Finally, the HCV RNA genome itself, particularly the IRES element, is being actively exploited as an antiviral target using antisense molecules and catalytic ribozymes. This review summarizes the most recent findings in each of these areas. Although not intended to be comprehensive, it should serve as a first resource for those individuals who desire updated information in this rapidly changing field.

Animals↗