Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019163 (hepatitis B)
 38,309 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several investigators have reported a significantly reduced CD4/CD8 ratio, as defined by monoclonal antibodies, in the peripheral blood of Caucasian patients with chronic active hepatitis B (CAHB). In Asian patients with chronic hepatitis B, quantitative analyses of subpopulations of peripheral blood lymphocytes have not been able to confirm these findings. In this work, we analysed the frequency of peripheral blood lymphocyte subsets in 10 Chinese patients with histologically proven CAHB and seven healthy Chinese individuals. Four of the 10 CAHB patients received combined prednisolone/interferon-alpha2b (IFN-alpha2b) therapy. Peripheral blood samples were consecutively collected for analysis of lymphocyte subpopulations using an indirect immunofluorescence (IF) method, and hepatitis B virus (HBV) DNA was quantified by a chemiluminescent, molecular-hybridization assay. Peripheral blood mononuclear cells from seven Chinese control individuals comprised 63 +/- 3% CD3+ cells, of which 41 +/- 4% were of CD4+ and 23 +/- 2% of CD8+ subsets. The mean CD4/CD8 ratio in the healthy controls was 1.9 (95% confidence interval = 1.1-2.7). The CD4/CD8 ratios were significantly reduced (P < 0.01) in the 10 patients with chronic hepatitis B, compared with those of the controls, owing to a significant increase in the number of CD8+ cells (P < 0.005). During the treatment with prednisolone, a significant increase in the CD4/CD8 ratio was observed in all treated patients. This increase was mainly caused by a decrease in the number of CD8+ cells and was accompanied by an increase in serum HBV DNA levels, which peaked during the latter part of the prednisolone cycle. During the treatment with IFN-alpha2b, a second increase in the CD4/CD8 ratio was observed, which was caused by an increase in CD4+ cells. A marked decrease in viral load was observed, during treatment with IFN-alpha2b, in patients with HBV DNA levels below 10 000 pg ml-1. Our data indicate that the CD4/CD8 ratios in Chinese CAHB patients do not differ from those of Caucasian patients with CAHB, when analysed using similar methods for the enumeration of lymphocyte subsets. Profound effects on cellular distribution and viral replication were noted during the combined prednisolone/IFN-alpha2b therapy. Additional studies of the modulatory effect of the combined therapy on the distribution of lymphocyte subsets and cytokine profiles in relation to the therapeutic outcome of HBV infection are warranted.
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PMID:Quantitative monitoring of serum hepatitis B virus DNA and blood lymphocyte subsets during combined prednisolone and interferon-alpha therapy in patients with chronic hepatitis B. 1060 34

It is well known that hepatitis B virus infections can be transient or chronic, but the basis for this dichotomy is not known. To gain insight into the mechanism responsible for the clearance of hepadnavirus infections, we have performed a molecular and histologic analysis of liver tissues obtained from transiently infected woodchucks during the critical phase of the recovery period. We found as expected that clearance from transient infections occurred subsequent to the appearance of CD4(+) and CD8(+) T cells and the production of interferon gamma and tumor necrosis factor alpha in the infected liver. These events were accompanied by a significant increase in apoptosis and regeneration of hepatocytes. Surprisingly, however, accumulation of virus-free hepatocytes was delayed for several weeks following this initial influx of lymphocytes. In addition, we observed that chronically infected animals can exhibit levels of T-cell accumulation, cytokine expression, and apoptosis that are comparable with those observed during the initial phase of transient infections. Our results are most consistent with a model for recovery predicting replacement of infected hepatocytes with regenerated cells, which by unknown mechanisms remain protected from reinfection in animals that can be cured.
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PMID:Apoptosis and regeneration of hepatocytes during recovery from transient hepadnavirus infections. 1062 61

Persistent infections with viruses such as HIV, Epstein-Barr virus, cytomelagovirus, and hepatitis B and C viruses continue to be major human health problems. Immunocytotherapy for persistent viral infections has proven successful in animal models but less effective in humans. While the requirement of antigen-specific CD8(+) T cells is known, the precise role of CD4(+) T cells as regards specific priming, numbers needed, and interaction with CD8(+) T cells is less clear. To address these issues, we used a mouse model of persistent virus infection in which adoptive transfer of T cells effectively purges virus from all tissues. We demonstrate that (1) inclusion of antigen-specific CD4(+) in addition to CD8(+) T cells is mandatory for efficient and long-term virus control. Neither naive nor CD4(+) T cells with specificity for a different virus are sufficient. (2) The minimal numbers of virus-specific T cells required for virus clearance from sera and tissues are 350,000 virus-specific CD8(+) and 7000 virus-specific CD4(+) T cells or approximately 5 x 10(7) CD8(+) and as few as 1 x 10(6) CD4(+) T cells per square meter of body surface area, a CD8:CD4 ratio of 50:1. (3) Production of interferon-gamma, obligatory for resolution of persistent infection, is dependent on the interaction of virus-specific CD4(+) and CD8(+) T cells. (4) Maintenance of CD8(+) T cell effector functions after adoptive transfer is directly proportional to the amount of cotransferred, virus-specific CD4(+) T cells.
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PMID:Defining parameters for successful immunocytotherapy of persistent viral infection. 1063 12

Preventing hepatitis B by vaccination is essential in HIV-infected patients (higher progression rate of HBV infection to chronicity, lower rate of serum HBe Ag loss). However, it has been shown a decreased anti-HBs response in these individuals after a standard vaccination (3 doses of 20 micrograms). Thus, we tested the hypothesis that doubling the number of hepatitis B vaccine injections might increase anti-HBs response rate. HIV-infected patients with CD4 > 200/microliter, who were on stable antiretroviral treatment, as well as seronegative for HBV markers, and who have never been vaccinated against HBV, were given 3 intramuscular injections of Genhevac B 20 micrograms at 1 month intervals. Initial non responders were given 3 additional monthly injections. Anti-HBs titer was followed. We also evaluated the effects on HIV-1 viral load. Twenty patients with a median CD4 cell count of 470/microliter were enrolled. The response rate after three 20 micrograms injections was 55% (11/20), lower in individuals with CD4 between 200 and 500/microliter (4/12 = 33.3%), compared to patients with CD4 above 500/microliter (7/8 = 87.5%, P = 0.02). Among 9 initial non-responders, only 2 did not respond to 3 additional doses; thus, the overall response rate was 90% (18/20). Geometric mean titers of anti-HBs were 133 IU/l and 77.5 IU/l, after 3 and 6 Genhevac doses, respectively (P = 0.38). One year later, only 10/17 (58.8%) patients had protective anti-HBs. Five patients experienced a significant viral load increase, transient in 3 cases. These preliminary results suggest that doubling the number of hepatitis B vaccinations in HIV-infected patients might significantly improve anti-HBs response rate; however, close monitoring of anti-HBs is necessary because of its short-lived persistence. The effects on HIV-1 viral load are limited.
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PMID:Increasing the number of hepatitis B vaccine injections augments anti-HBs response rate in HIV-infected patients. Effects on HIV-1 viral load. 1064 16

Persistent infections caused by such agents as the human immunodeficiency virus, hepatitis B virus, Epstein-Barr virus, etc., present formidable medical problems. A defining characteristic of these infections is that anti-viral cytotoxic T lymphocytes (CTL) may be lost or, if present, fail to clear the infection. Here we report a vaccination strategy which was successful in generating lytic CTL in persistently infected mice. Vaccination with an immunodominant CTL epitope derived from the nucleoprotein of lymphocytic choriomeningitis virus (LCMV) delivered in the form of a lipopeptide incorporating a universal CD4 helper epitope successfully induced lytic MHC-restricted CTL in mice persistently infected with LCMV since birth. However, induction of such CTL did not eliminate the virus, most likely because the CTL were generated at low frequencies and had 2 to 3 logs lower affinity than CTL generated in uninfected mice inoculated with the vaccine. Both CTL populations from either uninfected or persistently infected mice produced significant and similar amounts of interferon-gamma and IL-6. Vaccine-induced low-affinity CTL were still inadequate at complete removal of the virus when combined with LCMV-specific CD4 helper T lymphocytes. Thus, our results establish that CTL can be generated in persistently infected mice and that a crucial factor for clearing viral infection is the affinity of the CTL.
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PMID:Vaccination to treat persistent viral infection. 1070 49

Results from a multicentre, clinical trial of interferon-alpha2a (IFN-alpha2a) for the treatment of chronic hepatitis C are reported. Serum hepatitis C virus (HCV) RNA levels were monitored as follows: before, and 2 days after, the first administration of IFN-alpha2a; during and at the end of treatment; and 6 months after completion of therapy. Peripheral blood lymphocyte subpopulations were measured, by two-colour flow cytometry, before and 3 h after the first intramuscular (i.m.) administration of 9 mega units (MU) of IFN-alpha2a. Virological responders had a significantly lower pretreatment level of CD11+ CD8- lymphocytes. Biochemical responders had significantly lower pretreatment levels of CD11- CD8+, human leucocyte antigen (HLA) DR- CD4- and HLA DR- CD8+ populations, and a higher pretreatment HLA DR+ CD4- population. These pretreatment differences disappeared 3 h after the first i.m. administration of IFN-alpha2a. CD11- CD8+ and HLA DR+ CD8+ cell populations became significantly lower in virological responders 3 h after the first i. m. administration of IFN-alpha2a. HLA DR+ CD4+ cell populations were increased less in biochemical responders. Thus, T-lymphocyte subpopulations were different between responders and non-responders to IFN therapy and IFN-modulated host immunity. Multivariate analysis showed that the pretreatment CD11+ CD8- cell population was an independent predictive factor of response to therapy. On the other hand, patients whose serum HCV RNA cleared or decreased within the first 2 days of IFN-alpha2a therapy were more likely to achieve a virological response. This predictive factor, however, was not an independent factor by multivariate analysis. These results suggest that host immunity is an important factor in response to IFN therapy, and HCV clearance within the first 2 days is a good predictive factor of response.
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PMID:Immunological and virological predictors of outcome during interferon-alpha therapy of chronic hepatitis C. 1071 45

Clinical manifestations of hepatitis B virus (HBV) infection are a balance between viral and host factors. The immune response against any virus consists of a coordinated defence of innate immunity and acquired, virus-specific immunity. In acute HBV, immune responses associated with recovery include vigorous, polyclonal CD4 T cells directed against multiple epitopes within HBV; antibodies directed against surface envelope proteins (anti-HBs), the development of which requires the presence of a CD4 response; and HBV-specific cytotoxic T lymphocytes (CTLs). HBV-specific CTLs can induce death of infected hepatocytes as well as produce cytokines. Most individuals with acute HBV recover without evidence of massive liver destruction; this, plus evidence from transgenic animal models, suggests that these cytokines produced by T cells play an important role in controlling HBV replication. Individuals who fail to mount a vigorous response in acute HBV develop chronic infection. In these cases, the persisting ineffective immune response appears to be responsible for liver damage and is likely to initiate the process of hepatic fibrosis. Based on our current understanding of the immune response in acute and chronic HBV, several groups are investigating the prospect of manipulating the immune response in chronic HBV.
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PMID:The immunopathogenesis of HBV infection. 1072 52

The lymphocyte activation gene-3 (LAG-3) product is a MHC class II ligand that has been used in vivo to stimulate MHC class II+ APCs to increase tumor-specific immune responses. We investigated whether LAG-3 could also play an adjuvant role in vivo for the induction of humoral and CD4 or CD8 cell-mediated immune responses when immunizing mice with a particulate (hepatitis B surface Ag) or soluble (OVA) Ag. In both cases, coadministration of 1 microg of a soluble fusion protein between murine LAG-3 and the Fc fraction of a murine IgG2a mAb (mLAG-3Ig) as a vaccine adjuvant induced or increased CTL responses to the corresponding MHC class I-restricted peptide. In addition, splenocytes of mice vaccinated with either the particulate or soluble Ag plus mLAG-3Ig exhibited a significantly greater proliferative response than did splenocytes of mice immunized with Ag and a control Ig molecule. Similarly, these splenocytes had a greater Th1- but not Th2-type cytokine response. Finally, mice immunized with Ag plus mLAG-3Ig produced higher titers of Abs than mice immunized with Ag and a control Ig molecule. Thus, these data provide evidence of a novel means of improving the immunogenicity of subunit vaccines.
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PMID:A soluble lymphocyte activation gene-3 molecule used as a vaccine adjuvant elicits greater humoral and cellular immune responses to both particulate and soluble antigens. 1082 Feb 32

Serum TT virus (TTV) DNA was determined in 83 human immunodeficiency virus type 1 (HIV 1) infected mothers [46 intravenous drug user and 37 non-intravenous drug user women] and their infants. Twenty-nine (34.9%) mothers were TTV infected. Infection was more frequent among intravenous drug user than non-intravenous drug user mothers [21/46 (45.6%) vs. 8/37 (21.6%); relative risk (RR): 2.1; 95% confidence limits (95% CL): 1.1-4.2; P = 0.023] and among intravenous drug users who carried on injecting than in those who had given it up [10/14 (71.4%) vs. 11/32 (34.3%); RR: 2.1 (95%CL: 1.2-3.7); P = 0. 021]. Infection was not related to age, CD4-positive T-lymphocyte counts, HIV 1 load, hepatitis B (HBV), G/GB-C (GBV-C/HGV), C (HCV) virus exposure. Eight (27.5%) infants born to TTV infected (but none of those born to TTV uninfected) mothers were TTV infected at a median age of 1.5 (range: 0.6-2.8) months. Infants born by vaginal/emergency caesarean delivery were more frequently infected than those born by elective caesarean delivery [7/16 (43.7%) vs. 1/13 (7.6%); RR: 2.1; 95%CL: 1.2-3.5; P = 0.033]. Infection in infants was not related to maternal CD4-positive T-lymphocyte counts, HIV 1 load, and HIV 1, HBV, GBV-C/HGV, or HCV transmission. No infant became TTV infected thereafter. No TTV infected child [follow-up: 31 (median; range: 6-60) months] showed signs of liver disease; five infants cleared TTV DNA after 22 (median; range: 6-60) months. TTV infection in HIV 1 infected women is prevalently related to intravenous drug user. The findings suggest that infants may acquire TTV at birth. Infection may persist without evident liver disease.
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PMID:TT virus infection in human immunodeficiency virus type 1 infected mothers and their infants. 1086 44

The therapeutic goals in chronic hepatitis B are to prevent or decrease cirrhosis and hepatocellular carcinoma in patients with pre-cirrhotic or early cirrhotic disease and to stabilise patients with end-stage cirrhosis. Lamivudine is an oral nucleoside analogue that suppresses hepatitis B virus (HBV) replication, and so may achieve both these treatment objectives. The active 5'-triphosphate metabolite of lamivudine has two modes of viral suppression. First, it mimics deoxycytidine triphosphate and is incorporated into newly synthesised HBV DNA to cause chain termination. Second, it demonstrates competitive inhibition of viral DNA-dependent and RNA-dependent DNA polymerase activity (i.e., reverse transcriptase activity). Lamivudine may, therefore, act at four possible stages during HBV replication: reverse transcription of pre-genomic mRNA into nascent minus-strand DNA; formation of plus strand DNA from nascent minus-strand DNA; completion of double-stranded DNA; and formation of covalently closed circular DNA. In clinical studies, lamivudine therapy reduced serum HBV DNA and this was associated with significant improvements in liver histology and significant and sustained enhancement of the proliferative CD4-mediated response to HBeAg and hepatitis B core antigen (HBcAg), and an increased frequency of HBeAg-specific T cells. HBV DNA concentrations often returned to pre-treatment values when therapy ended prior to the loss of hepatitis B e antigen (HBeAg). Although the emergence of HBV variants with a mutation in the YMDD (tyrosine-methionine-aspartate-aspartate) motif has been observed, such variants show reduced susceptibility to lamivudine due to limited replication competence, and their emergence is not a signal to cease lamivudine therapy. In conclusion, viral suppression with lamivudine offers a means of disease improvement and immunological control in chronic hepatitis B.
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PMID:Profound suppression of hepatitis B virus replication with lamivudine. 1086 48


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