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1.
Arch Virol ; 159(10): 2699-704, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24796555

ABSTRACT

Studies have identified certain mutations in the 2B and 2C proteins of hepatitis A virus (HAV) as being essential for efficient growth in cultured cells, and it is assumed that these mutations contribute to the attenuated phenotype. We found that mutations supporting cell culture growth already exist in wild-type HAV populations. This suggests that these variants are not entirely generated de novo but are selected from the wild-type population. In a prolonged case of hepatitis A, we found that sequences associated with cell culture adaptation predominated later in infection. This might suggest selection of an attenuated virus population during a prolonged clinical infection.


Subject(s)
Adaptation, Physiological/genetics , Carrier Proteins/genetics , Hepatitis A virus/genetics , Viral Nonstructural Proteins/genetics , Base Sequence , Cell Line , Child, Preschool , Feces/virology , Hepatitis A Virus, Human , Hepatitis A virus/isolation & purification , Humans , Male , Mutation , RNA, Viral/analysis , Sequence Analysis, RNA , Virus Replication/genetics
2.
Arch Virol ; 159(7): 1723-33, 2014 Jul.
Article in English | MEDLINE | ID: mdl-24473712

ABSTRACT

NF-κB is activated by hepatitis B virus and hepatitis C virus and is assumed to contribute to viral persistence, leading to the development of hepatocellular cancer by inhibition of apoptosis mediated by cytotoxic T cells. Whether hepatitis A virus (HAV), which does not cause chronic infection, activates NF-κB is a topic of controversy. Here, we confirm that HAV activates NF-κB and show that HAV enhances the activation of NF-κB by poly(I-C), but it inhibits the activation of NF-κB by Newcastle disease virus (NDV), a paramyxovirus. In addition, HAV inhibits NF-κB activation induced by overexpressed MAVS (mitochondrial antiviral signaling protein). We conclude from these findings that NF-κB induction occurs in cells infected with HAV by dsRNA, independently of mitochondrial-transduced RIG-I/MDA-5 signaling, whereas the induction of NF-κB in cells infected by NDV is mediated by RIG-I signaling, independenly of viral dsRNA. This is supported by experiments in which the different RNA inducers of RIG-I and MDA-5 are sequestered and which also show that poly(I-C) and HAV, but not NDV, are functionally equivalent in inducing NF-κB activity. Furthermore, we demonstrate that HAV interferes with the protein kinase R (PKR) activity and PKR activation induced by dsRNA, and that HAV-induced activation of NF-κB therefore does not take place via the PKR-induced pathway. As assumed for hepatitis B and C virus infections, NF-κB activation could attenuate the effects of cytotoxic T cells and may contribute to prolonged as well as relapsing courses of hepatitis A.


Subject(s)
Hepatitis A virus/immunology , NF-kappa B/metabolism , Newcastle disease virus/immunology , RNA, Viral/metabolism , Animals , Cell Line , Gene Expression Regulation, Viral/immunology , Humans , NF-kappa B/genetics , RNA, Viral/genetics
3.
J Gen Virol ; 93(Pt 4): 754-760, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22170633

ABSTRACT

Hepatitis A virus (HAV) infections result in different courses of the disease, varying between normal, prolonged and relapsing. However, the reason for these heterogeneous clinical appearances is not understood. As HAV-anti-HAV IgA immunocomplexes (HAV-IgA) infect hepatocytes, IgA was postulated as a carrier supporting hepatotropic transport of HAV, and it was speculated that this carrier mechanism contributes to the various clinical outcomes. In this study, the IgA-carrier mechanism was investigated in a mouse model. We show that HAV-IgA immunocomplexes efficiently reached the liver not only in HAV-seronegative mice, but also, and this is in contrast to free-HAV particles, in immunized HAV-seropositive animals. This IgA-mediated transport of HAV to the liver in the presence of immunity depended on the stage of development of the immune response. We conclude that over a period of several weeks after infection, anti-HAV IgA is able to promote an enterohepatic cycling of HAV, resulting in continuous endogenous reinfections of the liver. Our experiments indicate that highly avid IgG antibodies, which are present at later times of the infection, can terminate the reinfections. However, the endogenous reinfections in the presence of a developing neutralizing immunity might contribute to prolonged as well as to relapsing courses of HAV infections. Furthermore, the results show that serum IgA may act as an infection protracting factor.


Subject(s)
Hepatitis A virus/immunology , Hepatitis A/immunology , Immunoglobulin A/immunology , Animals , Antibodies, Neutralizing/immunology , Hepatitis A/virology , Hepatitis A Vaccines/immunology , Hepatitis A virus/physiology , Humans , Immunity, Humoral/immunology , Liver/virology , Male , Mice , Mice, Inbred C3H , Recurrence
4.
J Gen Virol ; 89(Pt 7): 1593-1604, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18559929

ABSTRACT

Hepatitis A virus (HAV) antagonizes the innate immune response by inhibition of retinoic acid-inducible gene I-mediated and melanoma differentiation-associated gene 5-mediated beta interferon (IFN-beta) gene expression. This study showed that this is due to an interaction of HAV with mitochondrial antiviral signalling protein (MAVS)-dependent signalling, in which the viral non-structural protein 2B and the protein intermediate 3ABC recently suggested in this context seem to be involved, cooperatively affecting the activities of MAVS and the kinases TANK-binding kinase 1 (TBK1) and the inhibitor of NF-kappaB kinase epsilon (IKKepsilon). In consequence, interferon regulatory factor 3 (IRF-3) is not activated. As IRF-3 is necessary for IFN-beta transcription, inhibition of this factor results in efficient suppression of IFN-beta synthesis. This ability might be of vital importance for HAV, which is an exceptionally slow growing virus sensitive to IFN-beta, as it allows the virus to establish infection and maintain virus replication for a longer period of time.


Subject(s)
Hepatitis A virus/physiology , Interferon Regulatory Factor-3/antagonists & inhibitors , Interferon-beta/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism , Adaptor Proteins, Signal Transducing/antagonists & inhibitors , Animals , Cell Line , I-kappa B Kinase/antagonists & inhibitors , Macaca mulatta , Protein Serine-Threonine Kinases/antagonists & inhibitors , Transcription, Genetic
5.
J Gen Virol ; 86(Pt 10): 2747-2751, 2005 Oct.
Article in English | MEDLINE | ID: mdl-16186228

ABSTRACT

Although Hepatitis A virus (HAV) is transmitted by the faecal-oral route, its target for replication is the liver. Little is known of its interactions with cells of the gastrointestinal tract, and it is not known by which mechanisms HAV crosses the intestinal epithelium. In this study, it is shown that HAV associated with IgA is translocated from the apical to the basolateral compartment of polarized epithelial cells via the polymeric immunoglobulin receptor by IgA-mediated reverse transcytosis. The relevance of this mechanism, by which HAV-IgA complexes may overcome the intestinal barrier and contribute to infections of the liver, results from the fact that HAV-IgA complexes are infectious for hepatocytes and that significant amounts of intestinal HAV-IgA are present during acute infections, which are also partly transmitted. Besides supporting the primary infection, this mechanism may play a role in relapsing infections by establishing an enterohepatic cycle for HAV.


Subject(s)
Epithelial Cells/virology , Hepatovirus/metabolism , Immunoglobulin A/immunology , Receptors, Polymeric Immunoglobulin/physiology , Antigen-Antibody Complex/chemistry , Biological Transport , Cell Membrane/virology , Cell Polarity , Hepatovirus/immunology , Humans , Tumor Cells, Cultured
6.
J Virol ; 79(17): 10968-77, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16103148

ABSTRACT

Hepatitis A virus (HAV) antagonizes the innate immune response by inhibition of double-stranded RNA (dsRNA)-induced beta interferon (IFN-beta) gene expression. In this report, we show that this is due to an interaction of HAV with the intracellular dsRNA-induced retinoic acid-inducible gene I (RIG-I)-mediated signaling pathway upstream of the kinases responsible for interferon regulatory factor 3 (IRF-3) phosphorylation (TBK1 and IKKepsilon). In consequence, IRF-3 is not activated for nuclear translocation and gene induction. In addition, we found that HAV reduces TRIF (TIR domain-containing adaptor inducing IFN-beta)-mediated IRF-3 activation, which is part of the Toll-like receptor 3 signaling pathway. As IRF-3 is necessary for IFN-beta transcription, inhibition of this factor results in efficient suppression of IFN-beta synthesis. This ability of HAV seems to be of considerable importance for HAV replication, as HAV is not resistant to IFN-beta, and it may allow the virus to establish infection and preserve the sites of virus production in later stages of the infection.


Subject(s)
DNA-Binding Proteins/metabolism , Hepatitis A virus/pathogenicity , Hepatitis A/immunology , Interferon-beta/antagonists & inhibitors , RNA Helicases/metabolism , Signal Transduction , Transcription Factors/metabolism , Animals , DEAD Box Protein 58 , DEAD-box RNA Helicases , Hepatitis A/metabolism , Hepatitis A virus/growth & development , Humans , I-kappa B Kinase , Interferon Regulatory Factor-3 , Interferon-beta/genetics , Membrane Glycoproteins/chemistry , Membrane Glycoproteins/metabolism , Phosphorylation , Protein Serine-Threonine Kinases/metabolism , Protein Structure, Tertiary , Receptors, Cell Surface/chemistry , Receptors, Cell Surface/metabolism , Receptors, Immunologic , Toll-Like Receptor 3 , Toll-Like Receptors , Transcription, Genetic
7.
J Med Virol ; 72(1): 10-6, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14635005

ABSTRACT

The hepatitis A virus (HAV) is the most common etiological cause of acute hepatitis infections in humans in industrialized countries. Investigations into the viral load during HAV viremia, however, are rare. Therefore, correlation studies between viral load, biochemical, and specific serological markers have been undertaken. The group of sera comprised a series of multiple consecutive blood samples drawn from 11 patients at different times after onset of the disease. During the period up to 70 days after the onset of icterus, the individual range was at 1 x 10(3) to 3 x 10(4) HAV genome equivalents/ml. From day 75 until 120 after onset of the disease, the levels traced were at 10(3). In one case, it was possible to trace 1.25 x 10(4) genome equivalents/ml up to 180 days after onset of icterus and in two cases even up to 408 and 490 days viral load levels of 5 x 10(3) and 4 x 10(4) were detected, respectively. The same sera were used to measure IgM class antibodies to hepatitis A virus and the total anti-HAV. The results demonstrate that a direct correlation to peak levels of viral load exists with peak serum transaminase levels, but neither with peak anti-HAV IgM levels nor with total anti-HAV. Decreasing amounts of anti-HAV IgM tend to occur with decreasing amounts of HAV genome equivalents; and, vice versa, increasing amounts of total anti-HAV are accompanied by decreasing amounts of HAV genome equivalents. The longest duration of viremia was found in patients infected with HAV genotype IA.


Subject(s)
Hepatitis A/physiopathology , RNA, Viral/blood , Viral Load , Viremia/physiopathology , Acute Disease , Adult , Female , Genotype , Hepatitis A/virology , Hepatitis A Antibodies/blood , Hepatitis A Virus, Human/genetics , Hepatitis A Virus, Human/immunology , Hepatitis A Virus, Human/isolation & purification , Humans , Immunoglobulin M/blood , Male , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Viremia/virology
8.
J Virol ; 76(23): 11920-30, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12414934

ABSTRACT

The consequences of a hepatitis A virus (HAV) infection on cell-based antiviral responses and the interactions between virus and host cells resulting in persistent infections are poorly understood. In this report, we show that HAV does inhibit double-stranded (dsRNA)-induced beta interferon (IFN-beta) gene expression by influencing the IFN-beta enhanceosome, as well as dsRNA-induced apoptosis, which suggests that both effects may be connected by shared viral and/or cellular factors. This ability of HAV, which preserves the sites of virus production for a longer time, may allow the virus to establish an infection and may be the presupposition for setting up persistent infections. Our results suggest that the inhibitory effect of HAV on the cellular defense mechanisms might not be sufficient to completely prevent the antiviral reactions, which may be induced by accumulating viral dsRNA, at a later stage of infection. However, HAV seems to counteract this situation by downregulation of viral replication and in the following production of viral dsRNA. This ability of noncytopathogenic HAV acts dominantly on cytopathogenic HAV in trans. The downregulation might ensure the moderate replication which seems necessary for inhibition of the antiviral mechanisms by HAV and therefore for the persistent state of the HAV infection.


Subject(s)
Hepatitis A virus/immunology , Hepatitis A virus/pathogenicity , RNA, Double-Stranded/immunology , Animals , Apoptosis , Cell Line , Cytopathogenic Effect, Viral , Enhancer Elements, Genetic , Gene Expression , Hepatitis A/genetics , Hepatitis A/immunology , Hepatitis A/pathology , Hepatitis A/virology , Hepatitis A virus/genetics , Hepatitis A virus/physiology , Humans , Interferon-beta/biosynthesis , Interferon-beta/genetics , Macaca mulatta , RNA, Messenger/genetics , RNA, Messenger/metabolism , Virulence , Virus Replication
9.
J Virol ; 76(9): 4350-6, 2002 May.
Article in English | MEDLINE | ID: mdl-11932401

ABSTRACT

To analyze the pathogenetic mechanism of hematopoietic dysregulation associated with hepatitis A virus (HAV) infections, we studied the influence of HAV on monocyte (MO)-to-macrophage (MAC) maturation in vitro. Exposure of peripheral blood-derived mononuclear cells (MNC) to HAV led to diminished adherence of MO to plastic. Furthermore, HAV inhibited the ability of peripheral blood MO to differentiate toward MAC. Freshly isolated and 14-day-old MO cultures demonstrated reduced differentiation and decreased phagocytic capacity after challenge with HAV. Viral replication in MO/MAC cultures was confirmed by titration of infectious virus. We also determined the influence of HAV on the MO/MAC population in human long-term bone marrow cultures (LTBMCs). Inoculation of bone marrow MNC with HAV suppressed the establishment of an adherent stromal layer containing a reduced number of MAC. Furthermore, increased MO numbers in the nonadherent fraction of HAV-challenged LTBMCs are indicative of the disturbance of MO adherence. These findings suggest that HAV infection leads to a disorder of the mononuclear phagocytic system which may contribute to functional abnormalities of the bone marrow stroma.


Subject(s)
Cell Differentiation , Hepatitis A Virus, Human/pathogenicity , Macrophages/virology , Monocytes/cytology , Monocytes/virology , Cell Adhesion , Cells, Cultured , Hepatitis A/virology , Humans , Phagocytosis , Virus Replication
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