Molecular Biology and Inhibitors of Hepatitis A Virus

Debing, Yannick; Neyts, Johan; Thibaut, Hendrik Jan

doi:10.1002/med.21292

Cited by 32 publications

(28 citation statements)

References 155 publications

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“…Intracellular signals from RLRs are transmitted via an adaptor protein called mitochondrial antiviral signaling protein (MAVS), thus leading to the interferon regulatory factor 3 (IRF3)- and nuclear factor kappa B (NF-κB)-dependent production of type I and III interferons (IFNs) and proinflammatory cytokines 6, 7, 9 .…”

Section: Introductionmentioning

confidence: 99%

CXCL10 is produced in hepatitis A virus-infected cells in an IRF3-dependent but IFN-independent manner

Sung

Hong

Lee

et al. 2017

Sci Rep

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Acute hepatitis A caused by hepatitis A virus (HAV) infection is accompanied by severe liver injury in adult patients, and the liver injury is associated with the production of chemokines. Herein, we investigated the mechanism of how HAV infection induces the production of CXCR3 and CCR5 chemokines, such as CXCL10, CCL4 and CCL5. The production of CXCL10, CCL4 and CCL5 was markedly increased by HAV (HM-175/18f) infection in the culture of primary human hepatocytes and HepG2 cells. In particular, CXCL10 was produced in HAV-infected cells, not in neighboring uninfected cells. Moreover, these chemokines were significantly increased in the sera of acute hepatitis A patients. The production of IFN-λs was also robustly induced by HAV infection, and the blocking of secreted IFN-λs partially abrogated the production of CCL4 and CCL5 in HAV-infected cells. However, CXCL10 production was not decreased by the blocking of IFN-λs. Instead, CXCL10 production was reduced by silencing the expression of RIG-I-like receptor (RLR) signal molecules, such as mitochondrial antiviral signaling protein and interferon regulatory factor 3, in HAV-infected cells. In conclusion, HAV infection strongly induces the production of helper 1 T cell-associated chemokines, particularly CXCL10 via RLR signaling, even without secreted IFNs.Hepatitis A virus (HAV), which belongs to the family Picornaviridae, is transmitted via fecal to oral routes and is endemic in developing countries 1, 2 . Primary HAV infection tends to be asymptomatic in children but often causes acute hepatitis A (AHA) accompanied with severe liver injury in adults 3 . In AHA patients, the virus is eliminated after extensive immune-mediated liver injury 4 , and a lifelong immunity is established. Inactivated virus-based vaccines are now available in developed countries, and vaccination results in a dramatic decline of the incidence of AHA in these countries 2,5 .After the picornaviral infection of host cells, cytosolic viral dsRNA intermediates are recognized by melanoma differentiation-associated protein 5 (MDA-5), which belongs to retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), and endosomal dsRNA intermediates are recognized by Toll-like receptor 3 (TLR3) [6][7][8] . Intracellular signals from RLRs are transmitted via an adaptor protein called mitochondrial antiviral signaling protein (MAVS), thus leading to the interferon regulatory factor 3 (IRF3)-and nuclear factor kappa B (NF-κB)-dependent production of type I and III interferons (IFNs) and proinflammatory cytokines 6,7,9 .Despite this mechanism of IFN induction, HAV is known to minimally stimulate IFN response in the infected liver 3 . In chimpanzee studies, the amount of viral RNA is substantially higher in the HAV-infected liver compared to the hepatitis C virus (HCV)-infected liver. However, a type I IFN response is barely detected in the HAV-infected liver, whereas it is robustly evoked in the HCV-infected liver 10 . This may be because HAV has several mechanisms that strongly impair the induction of IF...

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Section: Introductionmentioning

confidence: 99%

CXCL10 is produced in hepatitis A virus-infected cells in an IRF3-dependent but IFN-independent manner

Sung

Hong

Lee

et al. 2017

Sci Rep

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“…Y P2 y P3, que comprenden proteínas no estructurales con funciones bioquímicas que soportan la replicación viral, como la 2A que interviene en la morfogénesis de la cápside, la 2C con función helicasa, la 3C con función proteasa y la 3D como ARN polimerasa (tabla1) (8,23). El virus se une al receptor celular HAVcr-1 (por la sigla en inglés de Hepatitis A virus cellular receptor 1), una glicoproteína integral de membrana clase I caracterizada por dominios similares a los de mucinas e inmunoglobulinas (5,20,24,25). Sin embargo, se propone que otros receptores deben intervenir en el proceso de unión y entrada del virus a la célula puesto que HAVcr-1 está presente en otras poblaciones celulares además de los hepatocitos (24,25).…”

Section: Descripción Del Genomaunclassified

“…El virus se une al receptor celular HAVcr-1 (por la sigla en inglés de Hepatitis A virus cellular receptor 1), una glicoproteína integral de membrana clase I caracterizada por dominios similares a los de mucinas e inmunoglobulinas (5,20,24,25). Sin embargo, se propone que otros receptores deben intervenir en el proceso de unión y entrada del virus a la célula puesto que HAVcr-1 está presente en otras poblaciones celulares además de los hepatocitos (24,25).…”

Section: Descripción Del Genomaunclassified

“…Se ha propuesto un segundo sitio de neutralización, conformado por los residuos 11 a 25 de la VP1 (TVSTEQNVPDPQVGI), 96 a 107 de la VP2 (GLLRYHTYARFG) y 110 a 121 de la VP3 (FWRGDLVFDFQV) (6,24,60), aunque este sitio se caracteriza por inducir una respuesta neutralizante débil (8). Cabe señalar que se ensayaron anticuerpos monoclonales específicos para enterovirus para los sitios antigénicos mencionados sin obtener ningún tipo de reacción; por ello se clasificó el VHA en el gé-nero Hepatovirus.…”

Section: Genotipos Del Vhaunclassified

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Infección por el virus de la hepatitis A: epidemiología y diversidad genética

Navas

Triana

2015

iatreia

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RESUMENLa infección por el virus de la hepatitis A es un problema global de salud pública. El virus está ampliamente distribuido y es la principal causa de hepatitis aguda de transmisión entérica en Latinoamérica. La partícula viral es estable en el medio ambiente y conserva su infectividad por varias semanas, lo que facilita su transmisión por agua y alimentos contaminados. Mundialmente se han descrito distintos patrones epidemiológicos, que pueden cambiar en el tiempo al modificarse variables socioeconómicas en la población como las condiciones sanitarias básicas y la vacunación. Esto deja al descubierto nuevas poblaciones susceptibles a la infección. En Latinoamérica se ha descrito la circulación del genotipo I y los subgenotipos A y B, pero se requieren más investigaciones que aporten el conocimiento necesario para gestionar planes de prevención y control para la disminución mundial de la prevalencia de la infección. Para este artículo se hizo una revisión de la literatura en las bases de datos SciELO, PubMed y ScienceDirect bajo los términos de búsqueda "Virus de la hepatitis A", "Epidemiología", "Seroprevalencia" e "Infección". De los resultados obtenidos se incluyeron únicamente las publicaciones en inglés y español que describieran estudios epidemiológicos y moleculares de interés en Latinoamérica. PALABRAS CLAVEEpidemiología; Hepatitis; Salud Pública; Virus de la Hepatitis A SUMMARY Hepatitis A virus infection: Epidemiology and genetic diversityHepatitis A virus infection is a global public health problem. The virus has a wide range of distribution and it is the main cause of acute hepatitis transmitted by the enteric route in

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“…They exhibit many similar biological features. For example, (1) their robust replication in vitro are induced by the cell-culture adapted mutations under experimental selection [7,8]; (2) They have a comparable genome structure, which encodes a single polyprotein that is processed by their viral or cellular proteases into separate viral proteins [9,10]; (3) Their infections in cells alter the morphology of endoplasmic reticulum (ER). e.g.…”

Section: Introductionmentioning

confidence: 99%

A visualizable hepatitis A virus and hepatitis C virus coinfection model in vitro: coexistence of two hepatic viruses under limited competition in viral RNA synthesis

Jiang

Long

2019

Preprint

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Hepatitis A virus (HAV) and hepatitis C virus (HCV) coinfection in patients usually leads to HCV suppression or clearance. Whether this suppression/clearance is caused by direct virus-virus interaction or indirect interactions is still unknown. Here, we present a robust and visualizable HAV/HCV coinfection model for investigating their interactions in vitro. We find that HAV superinfects HCV-persistently-infected Huh-7.5.1 cells without obvious virus-virus exclusion and vice versa, while there is a mild reciprocal viral interference in coinfection. Through single-cell scale confocal microscopy analysis and treating co-infected cells with rNTPs or antivirals e.g. Sofosbuvir, Simeprevir, and Ledipasvir, we find that HAV and HCV exploit cellular machinery in a compatible manner, but with reciprocal competition for rNTPs in their RNA synthesis. In conclusion, our findings reveal the absence of direct HAV-HCV interaction but the presence of indirect interaction, which may be due to limited competition in viral RNA synthesis. Therefore, we propose that suppression/clearance of HCV in HAV/HCV coinfected patients is probably due to indirect interactions e.g. viral competition or immunological interactions. Author summaryVirus-virus interactions could usually be categorized in three aspects: (1) direct interaction induced by interaction of viral gene or gene products; (2) indirect interaction mediated by immune response or (3) host environmental alteration. Hepatitis A virus (HAV) and hepatitis C virus (HCV) are two important causatives of human hepatitis. In patients, their coinfection often induces HCV suppression/clearance, and sometimes may lead to fulminant hepatitis. In this study, we find that a limited reciprocal viral interference occurs in HAV/HCV coinfection in vitro, which results from a viral competition of rNTPs in viral RNA synthesis. Our study provides a new paradigm of studying virus-virus interactions in single-cell scale. To our knowledge, we identify the rNTPs competition in virus coinfection for the first time by experiment, though several mathematical modelings have predicted the resource competition in virus coinfection.

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Molecular Biology and Inhibitors of Hepatitis A Virus

Cited by 32 publications

References 155 publications

CXCL10 is produced in hepatitis A virus-infected cells in an IRF3-dependent but IFN-independent manner

CXCL10 is produced in hepatitis A virus-infected cells in an IRF3-dependent but IFN-independent manner

Infección por el virus de la hepatitis A: epidemiología y diversidad genética

A visualizable hepatitis A virus and hepatitis C virus coinfection model in vitro: coexistence of two hepatic viruses under limited competition in viral RNA synthesis

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