Prolonged Gut Dysbiosis and Fecal Excretion of Hepatitis A Virus in Patients Infected with Human Immunodeficiency Virus.

Hepatitis A virus (HAV) causes transient acute infection, and little is known of viral shedding via the duodenum and into the intestinal environment, including the gut microbiome, from the period of infection until after the recovery of symptoms. Therefore, in this study, we aimed to comprehensively observe the amount of virus excreted into the intestinal tract, the changes in the intestinal microbiome, and the level of inflammation during the healing process. We used blood and stool specimens from patients with human immunodeficiency virus who were infected with HAV during the HAV outbreak in Japan in 2018. Moreover, we observed changes in fecal HAV RNA and quantified the plasma cytokine level and gut microbiome by 16S rRNA analysis from clinical onset to at least 6 months after healing. HAV was detected from clinical onset up to a period of more than 150 days. Immediately after infection, many pro-inflammatory cytokines were elicited, and some cytokines showed different behaviors. The intestinal microbiome changed significantly after infection (dysbiosis), and the dysbiosis continued for a long time after healing. These observations suggest that the immunocompromised state is associated with prolonged viral shedding into the intestinal tract and delayed recovery of the intestinal environment.

T cells protect against hepatitis A virus infection and limit infection-induced liver injury.

BACKGROUND & AIMS: Hepatitis A virus (HAV) is a common cause of enterically transmitted viral hepatitis. In non-immune individuals, infection results in typically transient but occasionally fulminant and fatal inflammatory liver injury. Virus-specific T cell frequencies peak when liver damage is at its zenith, leading to the prevalent notion that T cells exacerbate liver disease, as suspected for other hepatotropic virus infections. However, the overall contribution of T cells to the control of HAV and the pathogenesis of hepatitis A is unclear and has been impeded by a historic lack of small animal models. METHODS: Ifnar1-/- mice are highly permissive for HAV and develop pathogenesis that recapitulates many features of hepatitis A. Using this model, we identified HAV-specific CD8+ and CD4+ T cells by epitope mapping, and then used tetramers and functional assays to quantify T cells in the liver at multiple times after infection. We assessed the relationships between HAV-specific T cell frequency, viral RNA amounts, and liver pathogenesis. RESULTS: A large population of virus-specific T cells accumulated within the livers of Ifnar1-/- mice during the first 1-2 weeks of infection and persisted over time. HAV replication was enhanced and liver disease exacerbated when mice were depleted of T cells. Conversely, immunization with a peptide vaccine increased virus-specific CD8+ T cell frequencies in the liver, reduced viral RNA abundance, and lessened liver injury. CONCLUSION: These data show that T cells protect against HAV-mediated liver injury and can be targeted to improve liver health. LAY SUMMARY: Hepatitis A virus is a leading cause of acute viral hepatitis worldwide. T cells were thought to contribute to liver injury during acute infection. We now show that virus-specific T cells protect against infection and limit liver injury.

Mechanisms of Hepatocellular Injury in Hepatitis A.

Hepatitis A virus (HAV) infection is a common cause of acute viral hepatitis worldwide. Despite decades of research, the pathogenic mechanisms of hepatitis A remain incompletely understood. As the replication of HAV is noncytopathic in vitro, a widely accepted concept has been that virus-specific cytotoxic T cells are responsible for liver injury. However, accumulating evidence suggests that natural killer (NK) cells, NKT cells, and even non-HAV-specific CD8+ T cells contribute to liver damage during HAV infection. In addition, intrinsic death of virus-infected hepatocytes has been implicated as a cause of liver injury in a murine model of hepatitis A. Furthermore, genetic variations in host factors such as T cell immunoglobulin-1 (TIM1) and IL-18 binding protein (IL-18BP) have been linked to hepatitis A severity. This review summarizes the current knowledge of the mechanisms of hepatocellular injury in hepatitis A. Different mechanisms may be involved under different conditions and they are not necessarily mutually exclusive. A better understanding of these mechanisms would aid in diagnosis and treatment of diseases associated with HAV infection.

An outbreak of acute jaundice syndrome (AJS) among the Rohingya refugees in Cox's Bazar, Bangladesh: Findings from enhanced epidemiological surveillance.

In the summer of 2017, an estimated 745,000 Rohingya fled to Bangladesh in what has been described as one of the largest and fastest growing refugee crises in the world. Among numerous health concerns, an outbreak of acute jaundice syndrome (AJS) was detected by the disease surveillance system in early 2018 among the refugee population. This paper describes the investigation into the increase in AJS cases, the process and results of the investigation, which were strongly suggestive of a large outbreak due to hepatitis A virus (HAV). An enhanced serological investigation was conducted between 28 February to 26 March 2018 to determine the etiologies and risk factors associated with the outbreak. A total of 275 samples were collected from 18 health facilities reporting AJS cases. Blood samples were collected from all patients fulfilling the study specific case definition and inclusion criteria, and tested for antibody responses using enzyme-linked immunosorbent assay (ELISA). Out of the 275 samples, 206 were positive for one of the agents tested. The laboratory results confirmed multiple etiologies including 154 (56%) samples tested positive for hepatitis A, 1 (0.4%) positive for hepatitis E, 36 (13%) positive for hepatitis B, 25 (9%) positive for hepatitis C, and 14 (5%) positive for leptospirosis. Among all specimens tested 24 (9%) showed evidence of co-infections with multiple etiologies. Hepatitis A and E are commonly found in refugee camps and have similar clinical presentations. In the absence of robust testing capacity when the epidemic was identified through syndromic reporting, a particular concern was that of a hepatitis E outbreak, for which immunity tends to be limited, and which may be particularly severe among pregnant women. This report highlights the challenges of identifying causative agents in such settings and the resources required to do so. Results from the month-long enhanced investigation did not point out widespread hepatitis E virus (HEV) transmission, but instead strongly suggested a large-scale hepatitis A outbreak of milder consequences, and highlighted a number of other concomitant causes of AJS (acute hepatitis B, hepatitis C, Leptospirosis), albeit most likely at sporadic level. Results strengthen the need for further water and sanitation interventions and are a stark reminder of the risk of other epidemics transmitted through similar routes in such settings, particularly dysentery and cholera. It also highlights the need to ensure clinical management capacity for potentially chronic conditions in this vulnerable population.

Epidemiología y curso clínico de la hepatitis A en Cantabria antes y después del brote epidémico de junio 2016 / Epidemiology and clinical course of hepatitis A in Cantabria before and after the epidemic outbreak of June 2016

ANTECEDENTES Y OBJETIVOS: Desde junio de 2016 se han producido brotes de hepatitis A en diversos países europeos, afectando principalmente a hombres que tienen sexo con hombres (HSH). El objetivo del presente trabajo fue valorar su impacto clínico y epidemiológico en Cantabria. MATERIAL Y MÉTODOS: Se recogieron retrospectivamente todos los casos de hepatitis A diagnosticados en Cantabria entre enero de 2013 y septiembre de 2018. Se compararon dos periodos (enero 2013-mayo 2016 y junio 2016-septiembre 2018). RESULTADOS: Se diagnosticaron un total de 156 casos, objetivándose un aumento de la incidencia a partir de octubre de 2016. Con respecto al periodo 2013-2016, se observó una mayor proporción de varones (50,0 vs. 84,5%; p = 0,012) con una predominancia de la orientación sexual homosexual (80,6%) y una mayor frecuencia de transmisión sexual (0 vs. 48,3%; p = 0,061) en los pacientes del periodo 2016-2018. Desde el punto de vista clínico destacó que todos los casos de hepatitis grave ocurrieron en este último periodo. CONCLUSIONES: Nuestros resultados reafirman el elevado impacto clínico y epidemiológico del brote epidémico en Cantabria y ponen de relieve la necesaria optimización de las actuales medidas de prevención contra la hepatitis A

BACKGROUND AND OBJECTIVES: Since June 2016, there have been outbreaks of hepatitis A in various European countries, mainly affecting men who have sex with men (MSM). The aim of this study was to assess their clinical and epidemiological impact in Cantabria, Spain. MATERIAL AND METHODS: We retrospectively collected all cases of hepatitis A diagnosed in Cantabria between January 2013 and September 2018. We compared 2 periods: January 2013-May 2016 and June 2016-September 2018. RESULTS: A total of 156 cases were diagnosed, observing an increase in the incidence starting in October 2016. With regard to 2013-2016, we observed a higher proportion of men (50.0% vs. 84.5%; p=.012) with a predominance of the homosexual orientation (80.6%) and a higher rate of sexual transmission (0% vs. 48.3%; p=.061) for the patients in the 2016-2018 period. From the clinical standpoint, all cases of severe hepatitis occurred during this latter period. CONCLUSIONS: Our results reaffirm the high clinical and epidemiological impact of the epidemic outbreak in Cantabria and emphasizes the need for optimising the current prevention measures against hepatitis A

¿Es posible el control de los brotes de hepatitis A en hombres que tienen sexo con hombres? / Can hepatitis A outbreaks in men who have sex with men be controlled?

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Co-Occurrence of Hepatitis A Infection and Chronic Liver Disease.

Hepatitis A virus (HAV) infection occasionally leads to a critical condition in patients with or without chronic liver diseases. Acute-on-chronic liver disease includes acute-on-chronic liver failure (ACLF) and non-ACLF. In this review, we searched the literature concerning the association between HAV infection and chronic liver diseases in PubMed. Chronic liver diseases, such as metabolic associated fatty liver disease and alcoholic liver disease, coinfection with other viruses, and host genetic factors may be associated with severe hepatitis A. It is important to understand these conditions and mechanisms. There may be no etiological correlation between liver failure and HAV infection, but there is an association between the level of chronic liver damage and the severity of acute-on-chronic liver disease. While the application of an HAV vaccination is important for preventing HAV infection, the development of antivirals against HAV may be important for preventing the development of ACLF with HAV infection as an acute insult. The latter is all the more urgent given that the lives of patients with HAV infection and a chronic liver disease of another etiology may be at immediate risk.

Cost Comparison Between 2 Responses to Hepatitis A Virus Incidents in Restaurant Food Handlers-New York City, 2015 and 2017.

CONTEXT: While the New York City Department of Health and Mental Hygiene (DOHMH) can use agency-wide emergency activation to respond to a hepatitis A virus-infected food handler, there is a need to identify alternative responses that conserve scarce resources. OBJECTIVE: To compare the costs incurred by DOHMH of responding to a hepatitis A case in restaurant food handlers using an agency-wide emergency activation (2015) versus the cost of collaborating with a private network of urgent care clinics (2017). DESIGN: We partially evaluate the costs incurred by DOHMH of responding to a hepatitis A case in a restaurant food handler using agency-wide emergency activation (2015) with the cost of collaborating with a private network of urgent care clinics (2017) estimated for a scenario in which DOHMH incurred the retail cost of services rendered. RESULTS: Costs incurred by DOHMH for emergency activation were $65 831 ($238 per restaurant employee evaluated) of which DOHMH personnel services accounted for 85% ($55 854). Costs of collaboration would have totaled $50 914 ($253 per restaurant employee evaluated) of which personnel services accounted for 6% ($3146). CONCLUSIONS: Accounting for incident size, collaborating with the clinic network was more expensive than agency-wide emergency activation, though required fewer DOHMH personnel services.

Quasi-enveloped hepatitis virus assembly and release.

Hepatitis A virus (HAV) and hepatitis E virus (HEV) infections are the main causes for acute hepatitis worldwide. Both viruses had long been considered as nonenveloped viruses. However, recent work has uncovered that both viruses circulate in the bloodstream as membrane-cloaked, "quasi-enveloped" particles that are, surprisingly, infectious and likely the only form mediating virus spread within the host. The discovery of quasi-enveloped HAV and HEV particles has fundamentally changed the traditional view on the life cycle and pathogenesis of these viruses. However, because HAV and HEV are phylogenetically unrelated and their capsid assembly processes are quite distinct, it is not clear whether they use similar or different mechanisms for envelopment and exit. This review provides an overview of the current knowledge about the assembly and exit processes of HAV and HEV and perspectives for future studies.

Brote de Hepatitis A en Galicia durante 2016-2018 / Hepatitis A outbreak in Galicia during 2016-2018

OBJETIVO: En Galicia, la incidencia (I) de hepatitis A (HA) es baja y la susceptibilidad es del 51% en adultos (18-64 años). Entre 2016 y 2018 se incrementaron los casos, fundamentalmente en hombres. El objetivo de este estudio fue describir los casos de HA en Galicia en este periodo de brote (PB), compararlos con el periodo pre-brote (PPB), y describir las intervenciones realizadas. METODOS: Se realizó un estudio descriptivo de los casos de HA declarados entre 2016-2018 (PB), comparados con los del periodo previo (2010-2015, PPB). Se incluyeron los casos del Sistema de Notificación Obligatoria (por atención primaria, hospitalaria y microbiología) de 2010 a 2018. Se calculó el canal epidémico para el PPB, como media de casos/cuatrisemana para comparar casos observados/esperados. La incidencia (I) [casos por cada 100.000 habitantes (c/105h)] por sexo y edad se comparó con el PPB mediante el Riesgo Relativo (RR). Se enviaron mensajes con recomendaciones específicas a través de webs de referencia para hombres que tenían sexo con hombres (HSH). RESULTADOS: El brote duró 20 cuatrisemanas (septiembre de 2016 a marzo de 2018). La incidencia fue de 3 casos por cada 100.000 habitantes en hombres y 0,5 casos por cada 100.000 habitantes en mujeres. Frente al PPB, el RR-PB en hombres fue 4,8 (IC95%=4-7) y 20,4 (IC95%=5-87) entre 40 y 44 años. El 42% de los hombres respondieron tener relaciones con otros hombres (el 57% entre 20 y 30 años). A finales de 2016 se envió a través de Wapo (una de las webs de referencia de HSH) un mensaje con recomendaciones (fundamentalmente sobre vacunación), registrándose 331 entradas. CONCLUSIONES: La incidencia de HA aumenta en Galicia en el período 2016-2018 por un brote en HSH. La susceptibilidad se incrementa entre jóvenes, lo que hace necesario insistir en la vacunación de los grupos de riesgo

OBJECTIVE: In Galicia, the incidence (I) of hepatitis A (HA) is low and the susceptibility is 51% in adults (18-64 years). Between 2016 and 2018 the cases increased, mainly in men. We intend to describe the cases of HA in Galicia during this outbreak period (PB), compare them with the pre-outbreak period (PPB), and the interventions performed. METHODS: Descriptive study of the cases of HA declared between 2016-18 (PB), compared to those from the previous period (2010-2015, PPB). Cases recorded in the mandatory notification system (general practice, hospitalization and microbiology) from 2010 to 2018 were included. For the pre-outbreak period 2010-2015 (PPB) it was calculated the average of cases/four-week period to compare observed/expected cases; the incidence (I) [cases/100,000 inhabitants (c/105h)] by sex and age was compared with the PPB through the Relative Risk (RR). It were sent messages with recommendations through men who have sex with men (MSM) reference websites. RESULTS: The outbreak lasted 80 weeks (september of 2016 to march of 2018). The incidence was 3 cases/105h in men and 0.5 cases/105h in women. Compared to the PPB, the RR-PB in men was 4.8 (95%CI=4-7) and 20.4 (95%CI=5-87) in 40-44 years. 42% of men declared to have relationships with other men (57% in 20-30 years). At the end of 2016, a message with recommendations (specially vaccination) was sent via Wapo (promoted to MSM through one of its reference websites), where 331 entries were registered. CONCLUSIONS: HA's incidence, in Galicia, increased in 2016-2018 by an outbreak in MSM. We found an increased susceptibility among young people which makes necessary to insist on the vaccination of groups at risk

Superinfection of hepatitis A virus in hepatocytes infected with hepatitis B virus.

Hepatitis A virus (HAV) infection is a major cause of acute hepatitis including acute liver failure. Hepatitis B infection (HBV) occurs worldwide, with the highest rates in Asian and African countries, and there are several reports that HAV infection may have a more severe clinical course in patients with chronic HBV infection. We previously demonstrated that Japanese miso extracts have inhibitory effects on HAV replication. In the present study, we examined the replication of HAV and HBV in a hepatocyte superinfection model and the inhibitory effects of Japanese miso extracts on both viruses. According to the results, HAV infection inhibited HBV replication in superinfected hepatocytes, and Japanese rice-koji miso extracts had inhibitory effects on HAV replication. Our findings provide useful information for clinicians in managing HAV infection in patients with chronic HBV infection.

Disparities in hepatitis A virus (HAV) vaccination coverage among adult travelers to intermediate or high-risk countries: The role of birthplace and race/ethnicity.

BACKGROUND: While the hepatitis A virus (HAV) vaccine is recommended for United States (US) travelers to endemic regions, vaccination rates are lower among non-US-born adults and some racial minority groups. PURPOSE: We aimed to examine the relationship between birthplace, race and their interaction as predictors of self-reported HAV vaccination among adult travelers to high-risk countries (HRCs) through analysis of the National Health Interview Survey (NHIS), 2012-2015. METHODS: The study included 36,872 US adult participants in the 2012-2015 NHIS who traveled to countries where HAV is endemic. The main outcome was self-reported HAV vaccination (≥2 doses). Complex survey methods were applied to all models to provide statistical estimates that were representative of US adults. Multivariable logistic regression models adjusting for demographic, socioeconomic, medical, and access-to-care characteristics were fitted to examine the association between birthplace, race, race-by-birthplace (for interaction) and vaccination status. RESULTS: For adult travelers to HRCs, the adjusted odds ratio (AOR) of HAV vaccination was lower for non-US-born compared to US-born adults, AOR 0.86 (95% CI; 0.76, 0.98). For Hispanics, the AOR of HAV vaccination was 0.80 (95% CI; 0.70, 0.91) as compared to non-Hispanic-Whites. Furthermore, a significant qualitative interaction between birthplace and race was found (P-value 0.0005). Among non-Hispanic Blacks, the adjusted odds of HAV vaccination for non-US-born adults were 1.35 (95% CI; 1.06, 1.72) times the odds for US-born adults. In contrast, the AORs of HAV vaccination of non-US-born versus US-born adults were 36% (95% CI; 17%, 51%) and 30% (95% CI; 12%, 44%), lower for Asians and Hispanics, respectively. CONCLUSIONS: The association between birthplace and HAV vaccination status differs by race among travelers to HRCs, with US-born non-Hispanic Black and non-US-born Asian and Hispanic adults having lower odds of vaccination. Health care resources should be focused on these target populations to improve travel vaccination compliance.

Structural basis for neutralization of hepatitis A virus informs a rational design of highly potent inhibitors.

Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies-F4, F6, F7, and F9-are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 µM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development.

Anti-HAV evaluation and molecular docking of newly synthesized 3-benzyl(phenethyl)benzo[g]quinazolines.

Synthesized 3-benzyl(phenethyl)benzo[g]quinazolines (1-17) were evaluated in vitro to determine their effects against the anti-hepatitis A virus (HAV) using a cytopathic effect inhibition assay. Of the synthesized compounds, 16 and 17 showed considerably high anti-HAV activity, as indicated by their EC50 values of 27.59 and 18 µM, respectively, when compared to that of amantadine (37.3 µM), the standard therapeutic agent. In addition, they exhibited low cytotoxicity as indicated by their CC50 values, 290.63 and 569.45 µM, respectively. Compounds 1, 2, and 5 exhibited remarkable activity compared to the active compounds (16, 17) and amantadine. The selectivity index (SI) values were calculated and applied as a parameter for classifying the activity of the targets. In addition, molecular docking was performed to rationalize the SAR of the target compounds and analyze the binding modes between the docked-selected compounds and amino acid residues in the active site of the HAV-3C proteinase enzyme.

Very low prevalence of anti-HAV in Japan: high potential for future outbreak.

Since the early 21st century, almost all developed countries have had a very low hepatitis A virus antibody (anti-HAV) sero-prevalence profile, as sanitation conditions and health care facilities have been optimized to a universal standard. There has not been a report on anti-HAV prevalence among a large scale population in Japan since 2003. Therefore, this study aimed to investigate the current HAV status among the general population in Hiroshima. From each age and sex specific group, a total of 1,200 samples were randomly selected from 7,682 stocked serum samples from residents' and employees' annual health check-ups during 2013-2015. Total anti-HAV was detected using Chemiluminescent Enzyme Immunoassay. The overall anti-HAV sero-prevalence was 16.8%. In both males and females, anti-HAV prevalence among individuals between 20-59 years of age was as low as 0.0-2.0%, whilst that among 70 s was as high as 70.0-71.0%. A large number of residents aged under 60 are now susceptible to HAV infection. The cohort reduction trend of anti-HAV in Japan exposes the high possibility of mass outbreak in the future. HAV vaccine especially to younger generation and high risk population may prevent outbreak in Japan.

[Markers of hepatitis A in the monkeys of the Adlers primate center.]

Hepatitis A is a widespread viral infection. The HAV strains of "human" and "monkey" origin are similar in their morphological and antigenic properties, but differ genotypically. OBJECTIVES: The aim of this research was a comparative study of serological and molecular-genetic markers of HAV infection in monkeys born at the Adler Primate Center and in those imported from different countries. MATERIAL AND METHODS: Fecal samples (n = 313) and serum (n = 266) from various species of monkey using ELISA and RT-PCR were studied. RESULTS AND DISCUSSION: The frequency of anti-HAV-IgG was high (78.9%) in imported animals (vervet monkeys from Tanzania and cynomolgus monkeys from Vietnam) and as well as in various species of monkeys (rhesus monkeys, cynomolgus monkeys, green monkeys and papio hamadryas) of the Center (88.6%). At the same time, in the imported monkeys, the markers of "fresh" HAV infection (IgM-27.2%, Ag-HAV-16.7%, RNA-22.0%) were detected significantly more often (p> 0.05) than in monkeys kept at the Colony (IgM-7.5%, HAV-Ag - 5.2%, RNA - 3.6%). In general, anti-IgG reactivity ranged from 1.064 to 2.073 OD450, anti-IgM ranged from 0.546 to 1.059 OD450. The number of HAV-Ag was 0.496 - 1.995 OD450. RNA HAV only in rhesus monkeys and cynomolgys monkeys born at the Colony, as well as in imported vervet monkeys was detected. CONCLUSIONS: The data obtained indicate a wide circulation of HAV among monkeys born in the Adler Primate Center and among the imported animals. Markers of "fresh" HAV infection varied depending on the species of monkeys and their origin.

Status of adult immunity to hepatitis A virus in healthcare workers from a tertiary care hospital in north India.

Background & objectives: Humans are considered to be the principal host for hepatitis A virus (HAV) infection. In India, heterogeneous groups of susceptible individuals coexist in different regions. There has been a decline in antibody titres to HAV among young adults which may pose a major public health problem. The objective of this study was to assess the IgG anti-HAV level among healthcare workers (HCWs) in the age group of 20-60 yr and its association with the socio-demographic variables. Methods: Blood sample (2 ml) was collected under aseptic conditions from each participant followed by the preparation of serum and storing at -20°C. ELISA-based kits were used for the determination of IgG antibodies to HAV in the human serum samples. Results: Two hundred and fifty four HCWs were enrolled. IgG anti-HAV antibodies were detected in 97.2 per cent of the samples analyzed. No differences were observed in the levels of IgG anti-HAV antibody and education, income, occupation and socio-economic classes of the HCWs. A seropositivity rate of over 90 per cent was seen amongst all the socio-economic classes. Interpretation & conclusions: High levels of IgG protective antibodies were seen among the studied HCWs, hence HAV vaccination may not be required. It will be advisable to do a cost-benefit analysis of vaccination for HAV.

Murine Models of Hepatitis A Virus Infection.

Mechanistic analyses of hepatitis A virus (HAV)-induced pathogenesis have long been thwarted by the lack of tractable small animal models that recapitulate disease observed in humans. Several approaches have shown success, including infection of chimeric mice with human liver cells. Other recent studies show that HAV can replicate to high titer in mice lacking expression of the type I interferon (IFN) receptor (IFN-α/ß receptor) or mitochondrial antiviral signaling (MAVS) protein. Mice deficient in the IFN receptor show critical features of type A hepatitis in humans when challenged with human HAV, including histological evidence of liver damage, leukocyte infiltration, and the release of liver enzymes into blood. Acute pathogenesis is caused by MAVS-dependent signaling that leads to intrinsic apoptosis of hepatocytes.

History of the Discovery of Hepatitis A Virus.

Disease outbreaks resembling hepatitis A have been known since antiquity. However, it was not until World War II when two forms of viral hepatitis were clearly differentiated. After the discovery of Australia antigen and its association with hepatitis B, similar methodologies were used to find the hepatitis A virus. The virus was ultimately identified when investigators changed the focus of their search from serum to feces and applied appropriate technology.