Hepatitis: Planet Earth

Arichi T, Saito T, Major ME, Belyakov IM, Shirai M, Engelhard VH, Feinstone SM, Berzofsky JA. · Molecular Immunogenetics, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. · Proc Natl Acad Sci U S A. · Pubmed #10618412 links to  free full text

Abstract: DNA vaccines express antigens intracellularly and effectively induce cellular immune responses. Because only chimpanzees can be used to model human hepatitis C virus (HCV) infections, we developed a small-animal model using HLA-A2.1-transgenic mice to test induction of HLA-A2.1-restricted cytotoxic T lymphocytes (CTLs) and protection against recombinant vaccinia expressing HCV-core. A plasmid encoding the HCV-core antigen induced CD8(+) CTLs specific for three conserved endogenously expressed core peptides presented by human HLA-A2.1. When challenged, DNA-immunized mice showed a substantial (5-12 log(10)) reduction in vaccinia virus titer compared with mock-immunized controls. This protection, lasting at least 14 mo, was shown to be mediated by CD8(+) cells. Thus, a DNA vaccine expressing HCV-core is a potential candidate for a prophylactic vaccine for HLA-A2.1(+) humans.

Drazan KE. · Liver Transplant Program, Stanford University, Palo Alto, CA, USA. · Liver Transpl. · Pubmed #10915159 links to  free full text

Abstract: Hepatitis C infection (HCV) is an emerging epidemic. Liver specialists are managing this disease with limited scientific information about the underlying pathogenesis and treatment. The current review offers a molecular dissection of infection, a snapshot of the HCV life cycle, and emerging strategies for antiviral therapy.

Handa A, Brown KE. · Hematology Branch, National Heart, Lung and Blood Institute, Bldg 10/Rm 7C218, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1652, USA. · J Gen Virol. · Pubmed #10993934 links to  free full text

Abstract: A novel flavivirus, GB virus C (GBV-C)/hepatitis G virus (HGV), has been detected in chronic liver disease patients. It is known that the viral RNA can be detected in approximately 5% of American blood donors. However, the implications for liver disease and the sites of virus replication remain unknown. Possible sites of virus replication were studied by using cell lines and/or primary cells derived from human lymphoid cells, myeloid cells, hepatocytes and endothelial cells. RNA was detected by virus strand-specific RT-PCR and GBV-C/HGV antigen was detected with a rabbit polyclonal anti-E2 (envelope 2) antibody by Western blot analysis. Negative-strand RNA, representative of replicating virus, was detected in lymphoid and megakaryocytoid cell lines and primary vascular endothelial cells. In addition, an increase in virus titre over time was demonstrated and viral antigen was detected, and virus could be passaged to infect fresh cells. However, viral RNA or antigen could not be detected in any of the hepatocyte lines tested. These results indicate that the replication site of GBV-C/HGV is not primarily in hepatocytes and that detection of replicating virus in hepatic tissue may reflect virus replication in haematopoietic cells and/or vascular endothelial cells present in the liver.

Poaty-Mavoungou V, Onanga R, Yaba P, Delicat A, Dubreuil G, Mavoungou E. · Centre International de Recherches Médicales de Franceville, Gabon. · J Med Primatol. · Pubmed #11396861 No free full text.

Abstract: Six different species of nonhuman primates housed at the CIRMF Primate Center, cynomolgus monkeys (Macaca fascicularis), rhesus monkeys (Macaca mulatta), mandrills (Mandrillus sphinx), vervets (Cercopithecus aethiops pygerythrus), chimpanzees (Pan troglodyte) and baboons (Papio hamadryas), were evaluated for their natural killer cell activity and for the ability of their peripheral blood mononuclear cells to proliferate in response to known mitogens (concanavalin A, phytohemagglutinin and staphylococcal enterotoxin A) and to react with a panel of mouse monoclonal antibodies directed against human leukocyte surface antigens. Basic information on normal immune functions in these primates is important because of their use as experimental animal models for the study of human diseases such as acquired immunodeficiency syndrome (AIDS), hepatitis, loiasis and malaria.

Brown KE. · Virus Discovery Group, Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD 20892, USA. · J Gen Virol. · Pubmed #11602797 links to  free full text

This publication has no abstract.

Fiorucci S, Antonelli E, Mencarelli A, Palazzetti B, Alvarez-Miller L, Muscara M, del Soldato P, Sanpaolo L, Wallace JL, Morelli A. · Dipartimento di Medicina Clinica e Sperimentale, Clinica di Gastroenterologia ed Epatologia, Università degli Studi di Perugia, Italy. · Br J Pharmacol. · Pubmed #11834606 links to  free full text

Abstract: NCX-701 is a nitric oxide (NO)-releasing acetaminophen (APAP) derivative. In the present study we demonstrated that NCX-701 is as effective as APAP in controlling body temperature in a rat model of endotoxin-induced fever. Liver toxicity is a major complication of APAP overdosing. To investigate whether NCX-701 is hepatotoxic, BALB/C mice were injected with 100 - 500 mg kg(-1) APAP or NCX-701 alone or in combination (i.e. 500 mg kg(-1) of both compounds). Our results demonstrated that although APAP caused a dose-dependent liver injury, NCX-701 was completely devoid of liver toxicity. At the dose of 500 mg kg(-1) APAP caused an approximately 40 fold increase of AST plasma levels and extensive centrilobular necrosis. APAP and NCX-701 share the same metabolic pathway as demonstrated by the time-course of APAP-glucuronide concentrations in plasma and liver. NCX-701 was safe in mice with pre-existing chronic liver disease. Indeed, while C57BL6 transgenic mice expressing the hepatitis B virus (HBV) at the age of 8 months were significantly more susceptible to liver damage induced by APAP (500 mg kg(-1)) than their congenic littermates, treating HBV-transgenic mice with NCX-701, 500 mg kg(-1), caused no damage. Co-administration of NCX-701 at the dose 500 mg kg(-1) to mice treated with APAP, 500 mg kg(-1), completely protected against liver damage induced by APAP. APAP, but not NCX-701, upregulated liver Fas and Fas Ligand mRNA expression in vivo. Incubating mouse hepatocytes with APAP, but not with NCX-701, increased cell surface Fas expression and sensitized hepatocytes to death induced by challenge with a Fas-agonistic antibody. Collectively, these observations suggest that APAP toxicity is Fas mediated and that NCX-701 spares the liver by acting at several checkpoints in the Fas pathway.

He J, Innis BL, Shrestha MP, Clayson ET, Scott RM, Linthicum KJ, Musser GG, Gigliotti SC, Binn LN, Kuschner RA, Vaughn DW. · Walter Reed Army Institute of Research, Silver Spring, Maryland, USA. · J Clin Microbiol. · Pubmed #12454141 links to  free full text

Abstract: Hepatitis E virus (HEV) is an important cause of enterically transmitted hepatitis in developing countries. Sporadic autochthonous cases of hepatitis E have been reported recently in the United States and other industrialized countries. The source of HEV infection in these cases is unknown; zoonotic transmission has been suggested. Antibodies to HEV have been detected in many animals in areas where HEV is endemic and in domestic swine and rats in the United States. There is evidence supporting HEV transmission between swine and humans. Nevertheless, HEV has not been detected in wild rodents. We tested murid rodents and house shrews trapped in Nepal's Kathmandu Valley, where hepatitis E is hyperendemic, for HEV infection. The most commonly trapped species was Rattus rattus brunneusculus. Serum samples from 675 animals were tested for immunoglobulin G against HEV by enzyme-linked immunosorbent assay; 78 (12%) were positive, indicating acute or past infection. Antibody prevalence was higher among R. rattus brunneusculus and Bandicota bengalensis than in Suncus murinus. Forty-four specimens from 78 antibody-positive animals had sufficient residual volume for detection of HEV RNA (viremia) by reverse transcription-PCR. PCR amplification detected four animals (9%; three were R. rattus brunneusculus and one was B. bengalensis) with viremia. Phylogenetic analysis of the four genome sequences (405 bp in the capsid gene) recovered showed that they were identical, most closely related to two human isolates from Nepal (95 and 96% nucleotide homology, respectively), and distinct from HEV sequences isolated elsewhere. These data prove that certain peridomestic rodents acquire HEV in the wild and suggest that cross-species transmission occurs, with rodents serving as a virus reservoir for humans.

Yao ZQ, Waggoner SN, Cruise MW, Hall C, Xie X, Oldach DW, Hahn YS. · Beirne Carter Center for Immunology Research, Department of Microbiology and Pathology, University of Virginia, Charlottesville, VA 22908, USA. · J Virol. · Pubmed #16306613 links to  free full text

Abstract: T cells play an important role in the control of hepatitis C virus (HCV) infection. We have previously demonstrated that the HCV core inhibits T-cell responses through interaction with gC1qR. We show here that core proteins from chronic and resolved HCV patients differ in sequence, gC1qR-binding ability, and T-cell inhibition. Specifically, chronic core isolates bind to gC1qR more efficiently and inhibit T-cell proliferation as well as gamma interferon (IFN-gamma) production more profoundly than resolved core isolates. This inhibition is mediated by the disruption of STAT phosphorylation through the induction of SOCS molecules. Silencing either SOCS1 or SOCS3 by small interfering RNA dramatically augments the production of IFN-gamma in T cells, thereby abrogating the inhibitory effect of core. Additionally, the ability of core proteins from patients with chronic infections to induce SOCS proteins and suppress STAT activation greatly exceeds that of core proteins from patients with resolved infections. These results suggest that the HCV core/gC1qR-induced T-cell dysfunction involves the induction of SOCS, a powerful inhibitor of cytokine signaling, which represents a novel mechanism by which a virus usurps the host machinery for persistence.

Yao ZQ, Shata MT, Tricoche N, Shan MM, Brotman B, Pfahler W, Hahn YS, Prince AM. · Department of Microbiology and Pathology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, VA 22908, USA. · Virology. · Pubmed #16368125 No free full text.

Abstract: Chimpanzee is a unique animal model for HCV infection, in which about 50% of infections resolve spontaneously. It has been reported that the magnitude of T cell responses to HCV core in recovered chimpanzees is greater than that in chronically infected ones. However, the mechanism(s) by which the chimpanzees with resolved infection overcome core-mediated immunosuppression remains unknown. In this study, we examined the effect of HCV core on T cell responsiveness in chimpanzees with resolved and chronic HCV infection. We found that core protein strongly inhibited T cell activation and proliferation in chimpanzees with chronic infection, while this inhibition was limited in chimpanzees with resolved infection. Notably, the level of gC1qR, as well as the binding of core protein, on the surface of T cells was lower in recovered chimpanzees when compared to chimpanzees with chronic HCV infection. Intriguingly, the observed differences in gC1qR expression levels and susceptibility to core-induced suppression amongst HCV-chronically infected and recovered chimpanzees were observed prior to HCV challenge, suggesting a possible genetic determination of the outcome of infection. These findings suggest that gC1qR expression on the surface of T cells is crucial for HCV core-mediated T cell suppression and viral clearance, and that represents a novel mechanism by which a virus usurps host machinery for persistence.

He J, Innis BL, Shrestha MP, Clayson ET, Scott RM, Linthicum KJ, Musser GG, Gigliotti SC, Binn LN, Kuschner RA, Vaughn DW. · Walter Reed Army Institute of Research, Silver Spring, Maryland, USA. · J Clin Microbiol. · Pubmed #16517936 links to  free full text

This publication has no abstract.

Yao ZQ, Waggoner SN, Cruise MW, Hall C, Xie X, Oldach DW, Hahn YS. · Beirne Carter Center for Immunology Research, Department of Microbiology and Pathology, University of Virginia, Charlottesville, Virginia 22908, USA. · J Virol. · Pubmed #16873288 links to  free full text

This publication has no abstract.

Gattoni A, Parlato A, Vangieri B, Bresciani M, Derna R. · Department of Clinical and Experimental Medicine F Magrassi, II University of Naples School of Medicine, Napoli, Italy. · Clin Ter. · Pubmed #17051976 No free full text.

Abstract: PURPOSE: This review is aimed at exhaustively presenting and discussing the interferon-gamma (IFN-gamma), a cytokine that plays an important role in inducing and modulating an array of immune responses. DESIGN: A review of the most significant and recent clinical trials was performed. OVERVIEW: Although IFN-gamma has some antiviral activity, it is much less active in this regard than type I IFNs. IFN-gamma is involved in the regulation of nearly all phases of the immune and inflammatory responses, including the activation and differentiation of T cells, B cells, NK cells, macrophages, and others. It is therefore best regarded as a distint immunoregulatory cytokine. IFN-gamma secretion is a hallmark of Th1 lymphocytes. It is also secreted by nearly all CD8 T cells, by some Th0 cells, and by NK cells. Each of these cell types secretes IFN-gamma only when activated, usually as part of immune response and especially in response to IL-2 and IL-12. IFN-gamma production is inhibited by IL-4, IL-10, TGFbeta, glucocorticoids, cyclosporin A and FK506. Nearly all cell types express the heterodimeric receptor for IFN-beta and respond to this cytokine by increasing the surface expression of class I MHC proteins. As a result, virtually any cell in the vicinity of an IFN-beta-secreting cell becomes more efficient at presenting endogenous antigens and hence a better target for cytotoxic killing if it harbors an intracellular pathogen. Unlike the type I IFNs, IFN-gamma also increases the expression of class II MHC proteins on professional APCs, and so promotes antigen presentation to helper T cells as well. It also induces de novo expression of class II MHC proteins on venular endothelial cells and on some other epithelial and connective tissue cells that do not otherwise express them, thus enabling these cell types to function as temporary APCs at sites of intense immune reactions. The effector functions of NK cells are to lyse virus-infected cells and to secrete IFN-gamma, which activates macrofages to destroy phagocytosed microbes. The mechanism of NK cell-mediates cytolysis is essentially the same as that of cytolysis by CTLS. NK cells lyse virally infected cells before antigen specific CTLS came become fully active, that is, during the first few days after viral infection. NK cells are expanded and activated by cytokines of innate immunity, such as IL-12 and IL-15, and they kill infected cells, especially those that display reduced levels of class I molecoles. Some tumors, especially those of hematopoietic origin, are targets of NK cells, perlevels or types of class I MHC molecules. Therefore, IFN-gamma serves critical functions in innate immunity and in specific cell-mediated immunity (in addition, IFN activates neutrophilis and stimulates the cytolitic activity of NK cells). Many IFNs-gamma induced effects result in heigtened immune surveillance. CONCLUSIONS: IFN-gamma is a remarkable cytokine that orchestrates many distinct cellular programs through transcriptional control over large numbers of genes. Many IFNs-gamma-induced effects resulting in heightend immune surveillance and immune system function during infection have been discussed in this review. As the pathogens (microorganism with the potential to cause tissue injury or disease) augment local IFN-gamma production, and IFN-gamma augments the immune system response, an important function of IFN-gamma during in vivo infection is suggested. IFN-gamma is primarily secreted by activated T cells and natural killer cells, and can promote macrophage activation, mediate antiviral e antibacterial immunity, enhance antigen presentation, orchestrate activation of the innate immune system, coordinate lymphocyte-endothelium interaction, regulate Th1/Th2 balance, and control cellular proliferation and apoptosis.

Gattoni A, Parlato A, Vangieri B, Bresciani M, Derna R. · F Magrassi Department of Clinical and Experimental Medicine, II University of Naples School of Medicine, Napoli, Italy. · Clin Ter. · Pubmed #17147054 No free full text.

Abstract: PURPOSE: To discuss exhaustively: 1) the interferon-gamma in inducing and modulating of immune responses; 2) impairment of IFN-gamma production that plays an important role in the persistence of infection, chronicity of inflammation, evolution in fibrosis; 3) in "vivo" effects of combination treatment with recombinant interferon-gamma and alpha in chronic HCV-infection. DESIGN: We reviewed the most important recent studios on relationship between IFN-gamma and chronic course of hepatitis C. OVERVIEW: IFN-gamma is also a potent activator of macrophages. Exposure to IFN-gamma greatly enhances the microbicidal (and, to a lesser degree, citotoxic) activity of macrophages and induces them to secrete nitric oxide and monokines such as IL-1, IL-6, IL-8, and TFNalpha. It also activates neutrophils, NK cells, and vascular endothelial cells. Although IFN-gamma tends to promote the differentiation of B cells and CD8 T cells into immunologically active effectors, it does not promote lymphocyte proliferation. It enhances the activity of Thl cells, but inhibits the production of Th2 cells. IFN-gamma not only decreases the production of IL-4 by Th2 cells but also potently blocks the effects of IL-4 on B cells, promoting IgG1 production at the expense of IgE production. The inadequate Thl immunity as well as the weak HCV-specific T-cell response at the site of inflammation is associated with failure to clear the virus and a chronic course of disease. The production of IL-12 is critical for induction of Thl immunity, directed towards elimination of intracellular pathogenes and viruses. The core protein of HCV seems to have a suppressive action on IL-12 production at the transcriptional level. The specific Thl cell defect is correlated with insufficient Th and CTL responses, and lower production of type 1 cytokine (IL-2, IFN-gamma, lymphokine-activated killer cells). Taken together, these results are probably responsible for non-eradication of HCV infection. Particularly the effects of interferon-gamma may include inhibition of HCV virion production by an effect on viral RNA and protein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGF-beta, and an effect on HCV induced carcinogenesis. These data suggest an HCV-related cellular immune defect in patients with hepatitis C that can be restored in most patients by IL-12. CONCLUSIONS: The efficacy of IFN monotherapy in the HCV replicon system has been reported using IFN-alpha, IFN-gamma and IFN-beta. A recent clinical study to treatment chronic HCV involving sequential administration of IFN-alpha followed by IFN-gamma (IFN-alpha2b + IFN-gamma) showed a greater improvement over IFN monotherapy. This type of approach may lead to significant improvements in the therapeutic arsenal against chronic HCV infection.

Zhang Q, Wu G, Richards E, Jia S, Zeng C. · Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 101300, China. · Virol J. · Pubmed #17892576 links to  free full text

Abstract: BACKGROUND: The highly heterogenic characteristic of viruses is the major obstacle to efficient DNA amplification. Taking advantage of the large number of virus DNA sequences in public databases to select conserved sites for primer design is an optimal way to tackle the difficulties in virus genome amplification. RESULTS: Here we use hepatitis B virus as an example to introduce a simple and efficient way for virus primer design. Based on the alignment of HBV sequences in public databases and a program BxB in Perl script, our method selected several optimal sites for HBV primer design. Polymerase chain reaction showed that compared with the success rate of the most popular primers for whole genome amplification of HBV, one set of primers for full length genome amplification and four sets of walking primers showed significant improvement. These newly designed primers are suitable for most subtypes of HBV. CONCLUSION: Researchers can extend the method described here to design universal or subtype specific primers for various types of viruses. The BxB program based on multiple sequence alignment not only can be used as a separate tool but also can be integrated in any open source primer design software to select conserved regions for primer design.

Koay LB, Sun CS, Tsai SL, Lin CY. · Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan. · J Formos Med Assoc. · Pubmed #18194915 links to  free full text

Abstract: Genetic predisposition is known to be an important etiopathogenic factor of autoimmune hepatitis (AIH). HLA antigens associated with AIH have been well studied in Western countries and Japan, but there is no HLA typing data of AIH patients in Taiwan. We therefore investigated HLA phenotypes and their association with AIH patients and compared the results with those of normal subjects and patients with chronic liver disease. Group 1 consisted of 22 AIH patients. All were born in Taiwan with no history of blood transfusion. Group 2 consisted of 19 chronic liver disease patients. Group 3 consisted of 81 unrelated healthy subjects who were normal blood donors. All three groups were tested for HLA phenotypes (HLAA, B, C, DR, DQ) using the polymerase chain reaction-sequence specific probe method. The statistical method used was Fisher's exact test. We found that HLA-DQ5 was significantly more frequent in the AIH group compared to the control group (RR, 2.03; p = 0.034). Low frequency of A1 (n = 2/22), B8 (n = 1/22) and DR3 (n = 0/22) were noted compared to results from the West; only HLA-DR4 showed a higher rate in our AIH patients (n = 8/22). This is a preliminary report of our study of HLA antigens in AIH patients. Further investigation to characterize AIH patients into HLA allelic subgroups is being done.

Huang LM. · No affiliation provided · J Formos Med Assoc. · Pubmed #18400615 links to  free full text

This publication has no abstract.

Hui CK, Cheung WW, Leung KW, Cheng VC, Tang BS, Li IW, Luk JM, Lee NP, Kwong YL, Au WY, Yuen KY, Lau GK, Liang R. · Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Hong Kong, Special Administrative Region, China. · Hepatology. · Pubmed #18452145 No free full text.

Abstract: Whether preemptive anti- hepatitis B virus (HBV) therapy should be considered in all hepatitis B surface antigen (HBsAg)-negative patients with occult HBV infection receiving alemtuzumab containing chemotherapy is uncertain. We determined the outcome and effect on HBV-specific immunity of an alemtuzumab-containing chemotherapy regimen in occult HBV-infected patients. Twenty-one consecutive occult HBV-infected patients treated with an alemtuzumab containing chemotherapy regimen were studied. T cell reactivity to HBV antigens and -peptides were quantified by ELISpot and the T cell subset by flow cytometry. Six of the 21 patients (28.6%) developed HBsAg seroreversion. The median (range) time to development of HBsAg seroreversion after the end of chemotherapy was 1.8 months (0.2-2.3 months). Direct sequencing showed that the occult HBV infection of all six patients (100%) was reactivated. These six patients developed severe HBV-related hepatitis. At the end of follow-up, four of these six patients (66.7%) had become negative for HBsAg again. Recovery of CD4+ T cell count and CD4+T cell reactivity against hepatitis B core antigen (HBcAg) occurred 9 months after the end of chemotherapy. Loss of HBsAg occurred after recovery of the CD4+T cell count and increased CD4+T cell reactivity against HBcAg 9 months after the end of chemotherapy. CONCLUSION: An alemtuzumab-containing chemotherapy regimen is associated with a high risk of reactivation of occult HBV infection. Suppression of HBV immunity by an alemtuzumab-containing chemotherapy regimen would persist until 9 months after the end of chemotherapy. In occult HBV-infected patients receiving an alemtuzumab-containing chemotherapy regimen, preemptive anti-HBV therapy should be continued until 9 months after the end of chemotherapy, when recovery of HBV immunity has occurred.

Litovchick A, Szostak JW. · Howard Hughes Medical Institute, Center for Computational and Integrative Biology, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA. · Proc Natl Acad Sci U S A. · Pubmed #18824687 links to  free full text

Abstract: The hepatitis C virus (HCV) is a positive strand RNA flavivirus that is a major causative agent of serious liver disease, making new treatment modalities an urgent priority. Because HCV translation initiation occurs by a mechanism that is fundamentally distinct from that of host mRNAs, it is an attractive target for drug discovery. The translation of HCV mRNA is initiated from an internal ribosomal entry site (IRES), independent of cap and poly(A) recognition and bypassing eIF4F complex formation. We used mRNA display selection technology combined with a simple and robust cyclization procedure to screen a peptide library of >10(13) different sequences and isolate cyclic peptides that bind with high affinity and specificity to HCV IRES RNA. The best peptide binds the IRES with subnanomolar affinity, and a specificity of at least 100-fold relative to binding to several other RNAs of similar length. The peptide specifically inhibits HCV IRES-initiated translation in vitro with no detectable effect on normal cap-dependent translation initiation. An 8-aa cyclic peptide retains most of the activity of the full-length 27-aa bicyclic peptide. These peptides may be useful tools for the study of HCV translation and may have potential for further development as an anti-HCV drug.