Changing Epidemiology of Hepatitis A in China: Evidence From Three National Serological Surveys and the National Notifiable Disease Reporting System.

BACKGROUND AND AIMS: China has conducted surveillance for hepatitis A since 1990, and hepatitis A was highly-to-intermediately endemic in 1992 when a Chinese hepatitis A vaccine (HepA) was licensed and introduced as a family-pay vaccine. In 2008, HepA was introduced into the Expanded Program on Immunization as a free childhood vaccine. APPROACH AND RESULTS: Three nationally representative surveys conducted in 1992, 2006, and 2014 assessed hepatitis B serology. The 1992 survey included hepatitis A virus (HAV) serology, and we tested sera from the 2006 and 2014 surveys for HAV antibodies. We used surveillance, seroprevalence, and vaccination status data to describe the changing epidemiology of hepatitis A in China from 1990 through 2014. Before HepA licensure, anti-HAV seroprevalence was 60% at 4 years of age, 70% at 10 years, and 90% at 59 years; incidence was 52/100,000 and peaked at 4 years. In 2006, after >10 years of private sector vaccination, HepA coverage was <30% among children <5 years, and incidence was 5.4/100,000 with a peak at 10 years. In 2014, coverage was >90% among children under 5 years; incidence was 1.9/100,000. Individuals born before the national introduction of HepA (1988-2004) had lower anti-HAV seroprevalence than earlier and later birth cohorts. CONCLUSIONS: The incidence of hepatitis A declined markedly following HepA introduction and improvement of sanitation and hygiene. The emerging epidemiology is consistent with disease-induced immunity having been replaced by vaccine-induced immunity, resulting in a low incidence of hepatitis A. Catch-up HepA campaigns to close the immunity gap among the 1998-2004 birth cohorts should be considered.

Recent outbreaks of severe hepatitis A virus infections in Vienna.

To explore the epidemiology and clinical course of hepatitis A virus (HAV) infections at the Vienna General Hospital. We retrospectively identified patients who were tested positive for HAV-IgM at the Vienna General Hospital form Q1/2008 to Q3/2018. Our definition of severe HAV infection was AST and/or ALT > 5 × above the upper limit of normal (ULN); and liver dysfunction as (i) hepatic encephalopathy or ammonia > 100 µmol/L, (ii) coagulopathy with INR > 1.5, or (iii) jaundice with bilirubin > 5 mg/dL. A total of 578 HAV-IgM (+) were identified, including 31 (5.4%) and 38 (6.6%) without and with liver dysfunction, respectively. A proportional increase in severe HAV cases with and without liver dysfunction occurred in 2016/2017 with (21.5% (vs. 8.0% in the years before; p < 0.001). Thirty-seven (53.6%) patients with severe HAV were hospitalized, 6 (9%) required ICU support, and one patient received liver transplantation within 30 days. Patients with severe HAV and liver dysfunction were more often male (60.5 vs. 43.1%, p = 0.055) and younger (31.5 vs. 63 years, p < 0.001) as compared with other HAV-IgM (+) cases. The observed increase of severe HAV infections in Vienna in 2017 among young males, coincided with a multinational HAV outbreak among MSM. Our data suggests a higher likelihood of severe courses of hepatitis A in MSM. Vaccination against HAV should be recommended for risk groups.

Hepatitis A virus-induced hsa-miR-146a-5p attenuates IFN-ß signaling by targeting adaptor protein TRAF6.

Hepatitis A virus (HAV), a unique hepatotropic human picornavirus, is the causative agent of acute hepatitis A in humans. Some studies have shown that HAV antagonizes the innate immune response by disrupting interferon-beta (IFN-ß) signaling by viral proteins. However, whether microRNAs (miRNAs), a class of non-coding RNAs, are involved in the antagonism of IFN-ß induction upon HAV infection is still unclear. In this study, we investigated the effects and mechanisms by which HAV-induced miRNAs antagonize IFN-ß signaling. A variety of analytical methods, including miRNA microarray, RT-qPCR, dual-luciferase reporter assay, and Western blotting, were performed using HAV-infected cells. The results indicated that HAV infection upregulates the expression of hsa-miR-146a-5p, which in turn partially suppresses the induction of IFN-ß synthesis, thereby promoting viral replication. Mechanistically, TRAF6 (TNF receptor-associated factor 6), a key adaptor protein in the RIG-I/MDA5-mediated IFN-I signaling pathway, is targeted and degraded by hsa-miR-146a-5p. As TRAF6 is necessary for IFN-ß induction, inhibition of this protein attenuates IFN-ß signaling. Taken together, the results from this study indicated that HAV disrupts RIG-I/MDA5-mediated IFN-I signaling partially through the cleavage of the essential adaptor molecule TRAF6 via hsa-miR-146a-5p.

Human liver CD8+ MAIT cells exert TCR/MR1-independent innate-like cytotoxicity in response to IL-15.

BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells, the most abundant innate-like T cells in the human liver, can be activated by cytokines during viral infection without TCR stimulation. Here, we examined the mechanisms underlying TCR/MR1-independent innate-like cytotoxicity of cytokine-activated liver MAIT cells. We also examined the phenotype and function of MAIT cells from patients with acute viral hepatitis. METHODS: We obtained liver sinusoidal mononuclear cells from donor liver perfusate during liver transplantation and examined the effect of various cytokines on liver MAIT cells using flow cytometry and in vitro cytotoxicity assays. We also obtained peripheral blood and liver-infiltrating T cells from patients with acute hepatitis A (AHA) and examined the phenotype and function of MAIT cells using flow cytometry. RESULTS: IL-15-stimulated MAIT cells exerted granzyme B-dependent innate-like cytotoxicity in the absence of TCR/MR1 interaction. PI3K-mTOR signaling, NKG2D ligation, and CD2-mediated conjugate formation were critically required for this IL-15-induced innate-like cytotoxicity. MAIT cells from patients with AHA exhibited activated and cytotoxic phenotypes with higher NKG2D expression. The innate-like cytotoxicity of MAIT cells was significantly increased in patients with AHA and correlated with serum alanine aminotransferase levels. CONCLUSIONS: Taken together, the results demonstrate that liver MAIT cells activated by IL-15 exert NKG2D-dependent innate-like cytotoxicity in the absence of TCR/MR1 engagement. Furthermore, the innate-like cytotoxicity of MAIT cells is associated with liver injury in patients with AHA, suggesting that MAIT cells contribute to immune-mediated liver injury. LAY SUMMARY: Immune-mediated liver injury commonly occurs during viral infections of the liver. Mucosal-associated invariant T (MAIT) cells are the most abundant innate-like T cells in the human liver. Herein, we have identified a mechanism by which MAIT cells circumvent conventional T cell receptor interactions to exert cytotoxicity. We show that this innate-like cytotoxicity is increased during acute hepatitis A virus infection and correlates with the degree of hepatocyte injury.

Functions of human liver CD69+CD103-CD8+ T cells depend on HIF-2α activity in healthy and pathologic livers.

BACKGROUND & AIMS: Human liver CD69+CD8+ T cells are ~95% CD103- and ~5% CD103+. Although CD69+CD103+CD8+ T cells show tissue residency and robustly respond to antigens, CD69+CD103-CD8+ T cells are not yet well understood. METHODS: Liver perfusate and paired peripheral blood were collected from healthy living donors and recipients with cirrhosis during liver transplantation. Liver tissues were obtained from patients with acute hepatitis A. Phenotypic and functional analyses were performed by flow cytometry. Gene expression profiles were determined by microarray and quantitative reverse transcription PCR. PT-2385 was used to inhibit hypoxia-inducible factor (HIF)-2α. RESULTS: Human liver CD69+CD103-CD8+ T cells exhibited HIF-2α upregulation with a phenotype of tissue residency and terminal differentiation. CD103- cells comprised non-hepatotropic virus-specific T cells as well as hepatotropic virus-specific T cells, but CD103+ cells exhibited only hepatotropic virus specificity. Although CD103- cells were weaker effectors on a per cell basis than CD103+ cells, following T cell receptor or interleukin-15 stimulation, they remained the major CD69+CD8+ effector population in the liver, surviving with less cell death. An HIF-2α inhibitor suppressed the effector functions and survival of CD69+CD103-CD8+ T cells. In addition, HIF-2α expression in liver CD69+CD103-CD8+ T cells was significantly increased in patients with acute hepatitis A or cirrhosis. CONCLUSIONS: Liver CD69+CD103-CD8+ T cells are tissue resident and terminally differentiated, and their effector functions depend on HIF-2α. Furthermore, activation of liver CD69+CD103-CD8+ T cells with HIF-2α upregulation is observed during liver pathology. LAY SUMMARY: The immunologic characteristics and the role of CD69+CD103-CD8+ T cells, which are a major population of human liver CD8+ T cells, remain unknown. Our study shows that these T cells have a terminally differentiated tissue-resident phenotype, and their effector functions depend on a transcription factor, HIF-2α. Furthermore, these T cells were activated and expressed higher levels of HIF-2α in liver pathologies, suggesting that they play an important role in immune responses in liver tissues and the pathogenesis of human liver disease.

Hepatitis A Outbreak Among Men Who Have Sex With Men, Yokohama, Japan, January to May 2018.

Between January and May in 2018, 17 male cases of hepatitis A were reported in Yokohama, Japan. Of these, 14 identified as men who have sex with men. The viral sequence in this outbreak was same as that of the recent European and Taiwanese outbreaks strain.

Outbreaks of Hepatitis A in US Communities, 2017-2018: Firsthand Experiences and Operational Lessons From Public Health Responses.

Objectives. To identify and analyze common challenges from multiple US communities affected by the hepatitis A epidemic beginning in March 2017, and to identify operational lessons to support preparedness for similar future public health emergencies.Methods. We conducted semistructured interviews with health officials from 9 city or county health departments to collect the firsthand experience of public health responders. We collected data from January to October 2018 via teleconference. Key informants, whom we purposefully sampled, were senior public health officials who were directly involved in outbreak response or in preparing for potential hepatitis A outbreaks in their communities.Results. Several themes emerged during these discussions, including common challenges and solutions pertaining to sanitation and hygiene infrastructure, hepatitis A vaccination, health workforce availability and surge capacity, communication and stigma, and partnerships and coordination with local law enforcement and other stakeholders.Conclusions. By generating key, evidence-based operational lessons, this study can inform response activities in localities currently experiencing outbreaks as well as community preparedness for possible future outbreaks due to the presence of similar at-risk populations.

Hepatitis A outbreak affecting men who have sex with men (MSM) in South Italy.

From April to October 2017, 27 cases of Hepatitis A (HA), 22 male and 5 female, were reported in Cosenza (South Italy). The median age of cases was 32 years (range 3-49 years). Out of 21 male adults, 14 were identified as men who have sex with men (MSM). Phylogenetic analysis was conducted in 15 cases and revealed two distinct sequences of genotype IA linking to clusters recognised in MSM in other European countries in 2016; genotype IB was recognized in only 2 cases. The report confirms that HA is an emerging issue among MSM. As suggested by the WHO, in countries with low HAV circulation, vaccination programmes should be tailored on local epidemiological patterns to prevent outbreaks among high risk groups and eventual spill-over of the infection into the general population.

Hepatitis A outbreak in Barcelona among men who have sex with men (MSM), January-June 2017: A hospital perspective.

BACKGROUND & AIMS: Acute hepatitis A is transmitted mainly via the faecal-oral route and/or contaminated aliment. Furthermore, several outbreaks in the men who have sex with men (MSM) population classified hepatitis A as a sexually transmitted disease (STD). We aimed to clarify an ongoing hepatitis A outbreak in Barcelona with respect to patients' characteristics and viral phylogenetic analysis. METHODS: We prospectively analyzed 46 cases of hepatitis A infection that were registered in our hospital between January and June 2017. We evaluated demographics data, risk factors, presenting symptoms, sexual orientation, comorbidities and further STD infections. The phylogenetic correlation of the current circulating viruses among them and other hepatitis A strains was assessed by sequencing of the VP1/P2A region. RESULTS: Most patients were male (44, 96%) with median age 33.5 years (range 28-50). Thirty-one (67%) were MSM and 18 (39%) required hospitalization. Molecular phylogenetic analyses revealed that all patients were infected by hepatitis A subgenotype IA strains. Moreover, current strains comprised 3 distinct clusters, previously reported in ongoing outbreaks in the United Kingdom, Berlin and the Netherlands. However, these strains were phylogenetically diverse to those previously reported in Barcelona metropolitan region. CONCLUSIONS: Ongoing hepatitis A outbreak in Barcelona affects primarily the MSM community and is phylogenetically linked to current hepatitis A outbreaks described in other European countries. As a result of the high admission rate, these outbreaks may impact the admission pattern of referral liver units. Control measures, for example vaccinations programs tailored to the MSM community, must be taken to control further spreading.

Incidence of acute hepatitis A among HIV-positive patients during an outbreak among MSM in Taiwan: Impact of HAV vaccination.

BACKGROUND: An unprecedented outbreak of acute hepatitis A has occurred among MSM in Taiwan since June 2015. We aimed to describe the seroepidemiology of HAV infection and to investigate the relationship between HAV vaccination and the incidence of acute hepatitis A among HIV-positive patients at the largest designated hospital for HIV care during the outbreak. METHODS: Between 2012 and 2016, the HAV serostatus, vaccination history and clinical characteristics of HIV-positive patients were retrospectively reviewed. A case-control study was performed to identify the factors associated with acute hepatitis A. The trends of HAV vaccination rate and incidence of acute hepatitis A among HAV-seronegative patients were examined during the outbreak. RESULTS: During the 4.5-year period, 2088 HIV-positive patients with a mean age of 37.7 years and 90.2% being MSM were included. The overall HAV seroprevalence was 34.3%, which was significantly higher in older and non-MSM patients. The estimated incidence rate of acute hepatitis A was 52.6 cases per 1000 person-years of follow-up during the outbreak. The associated factors with acquiring acute hepatitis A were recent syphilis and having not received HAV vaccines. The HAV vaccination rate during the outbreak increased from 4.7% to 70.6% and the incidence rate of acute hepatitis A declined when up to 65% of the patients were immunized or tested positive for HAV. CONCLUSIONS: The seroprevalence of HAV infection was low in the younger HIV-positive individuals. Prevention of acute hepatitis A was achieved among HIV-positive, HAV-seronegative patients through HAV vaccination and increased herd immunity during the ongoing outbreak.

Spillover of a hepatitis A outbreak among men who have sex with men (MSM) to the general population, the Netherlands, 2017.

Since 2015, outbreaks of hepatitis A among men who have sex with men (MSM) have been reported worldwide. To examine the impact of these MSM outbreaks in the Netherlands, we combined notification and epidemiological data with sequence analysis. Our results show the hazards of outbreaks within risk-groups spilling over into the largely susceptible general population. One third of the outbreak-related hepatitis A virus genotypes were detected in non-MSM cases.

Persistence of antibody to Hepatitis A virus 20 years after receipt of Hepatitis A vaccine in Alaska.

Hepatitis A vaccine is recommended for children ≥1 year old to prevent hepatitis A virus (HAV) infection. However, the duration of vaccine-induced immunity is unknown. We evaluated a cohort of Alaska Native persons 20 years after HAV vaccination. Children aged 3-6 years had been previously randomized to receive three doses of HAV vaccine (360 ELISA units/dose) at: (i) 0,1,2 months; (ii) 0,1,6 months; and (iii) 0,1,12 months. We measured anti-HAV antibody concentrations every 2-3 years; described geometric mean concentrations (GMC) and the proportion with protective antibody (≥20 mIU mL-1 ) over time; and modelled the change in GMC using fractional polynomial regression. Of the 144 participants, after 20 years 52 (36.1%) were available for the follow-up (17, 18, 17 children in Groups A, B and C, respectively). Overall, 46 (88.5%) of 52 available participants had anti-HAV antibody concentrations ≥20 mIU mL-1 , and overall GMC was 107 mIU mL-1 . Although GMC levels were lower in Group A (60; CI 34-104) than in Group B (110; CI 68-177) or Group C (184; CI 98-345) (B vs C: P=.168; A vs B/C: P=.011), there was no difference between groups after adjusting for peak antibody levels post-vaccination (P=.579). Models predicted geometric mean concentrations of 124 mIU mL-1 after 25 years, and 106 mIU mL-1 after 30 years. HAV vaccine provides protective antibody levels 20 years after childhood vaccination. Lower antibody levels in Group A may be explained by a lower initial peak response. Our results suggest a booster vaccine dose is unnecessary for at least 25-30 years.

Development of a peptide ELISA to discriminate vaccine-induced immunity from natural infection of hepatitis A virus in a phase IV study.

Hepatitis A virus (HAV) is a highly infectious agent that causes acute liver disease. The infection can trigger the production of antibodies against the structural and non-structural proteins of HAV. Nonetheless, vaccination with an HAV vaccine leads to the production of a primary antibody against the structural proteins. Because the non-structural proteins are only produced during active virus replication, there is no or very little antibody production against the non-structural proteins. However, the current commercial immunoassay cannot distinguish between antibodies produced during natural infection and those from vaccination against HAV. In our study, six immune-dominant epitopes from the non-structural proteins were designed, synthesized, linked together and cloned into pGEX-5X-1 plasmid. The recombinant protein was expressed in E. coli and purified by Ni2+-coated magnetic agarose beads. Then the purified recombinant protein was used as an ELISA antigen to detect antibodies for HAV non-structural proteins in serum samples. Seventy-seven attenuated and 89 inactivated vaccinated samples collected from our previous phase IV study of HAV vaccines were detected by peptide ELISA developed in this study. The mean OD450 value for the vaccination samples and acute infection samples were 0.529 (0.486 for the attenuated group and 0.567 for the inactivated group) and 1.187, respectively. According to the receiver operating characteristic (ROC) curve, the sensitivity and specificity of the peptide ELISA were 93.80% and 91.00%, respectively. This peptide ELISA was confirmed to discriminate vaccine-induced immunity from natural infection of HAV in a phase IV study with high sensitivity and specificity.

Cytotoxic effect of co-expression of human hepatitis A virus 3C protease and bifunctional suicide protein FCU1 genes in a bicistronic vector.

Recent reports on various cancer models demonstrate a great potential of cytosine deaminase/5-fluorocytosine suicide system in cancer therapy. However, this approach has limited success and its application to patients has not reached the desirable clinical significance. Accordingly, the improvement of this suicide system is an actively developing trend in gene therapy. The purpose of this study was to explore the cytotoxic effect observed after co-expression of hepatitis A virus 3C protease (3C) and yeast cytosine deaminase/uracil phosphoribosyltransferase fusion protein (FCU1) in a bicistronic vector. A set of mono- and bicistronic plasmid constructs was generated to provide individual or combined expression of 3C and FCU1. The constructs were introduced into HEK293 and HeLa cells, and target protein synthesis as well as the effect of 5-fluorocytosine on cell death and the time course of the cytotoxic effect was studied. The obtained vectors provide for the synthesis of target proteins in human cells. The expression of the genes in a bicistronic construct provide for the cytotoxic effect comparable to that observed after the expression of genes in monocistronic constructs. At the same time, co-expression of FCU1 and 3C recapitulated their cytotoxic effects. The combined effect of the killer and suicide genes was studied for the first time on human cells in vitro. The integration of different gene therapy systems inducing cell death (FCU1 and 3C genes) in a bicistronic construct allowed us to demonstrate that it does not interfere with the cytotoxic effect of each of them. A combination of cytotoxic genes in multicistronic vectors can be used to develop pluripotent gene therapy agents.

Hepatitis A among refugees, asylum seekers and migrants living in hosting facilities, Greece, April to December 2016.

An increased number of hepatitis A cases among refugees, asylum seekers and migrants residing in hosting facilities in Greece were recorded between April and December 2016. In total, 177 laboratory-confirmed symptomatic cases were reported; of these, 149 (84%) occurred in hosting camps mostly among Syrian children under 15 years. All cases reported symptom onset after their entry into the country. Public health interventions focused on hygiene measures and vaccination.

An Outbreak of Acute Hepatitis Caused by Genotype IB Hepatitis A Viruses Contaminating the Water Supply in Thailand.

BACKGROUND: In 2000, an outbreak of acute hepatitis A was reported in a province adjacent to Bangkok, Thailand. AIMS: To investigate the cause of the 2000 hepatitis A outbreaks in Thailand using molecular epidemiological analysis. METHODS: Serum and stool specimens were collected from patients who were clinically diagnosed with acute viral hepatitis. Water samples from drinking water and deep-drilled wells were also collected. These specimens were subjected to polymerase chain reaction (PCR) amplification and sequencing of the VP1/2A region of the hepatitis A virus (HAV) genome. The entire genome sequence of one of the fecal specimens was determined and phylogenetically analyzed with those of known HAV sequences. RESULTS AND CONCLUSIONS: Eleven of 24 fecal specimens collected from acute viral hepatitis patients were positive as determined by semi- nested reverse transcription PCR targeting the VP1/2A region of HAV. The nucleotide sequence of these samples had an identical genotype IB sequence, suggesting that the same causative agent was present. The complete nucleotide sequence derived from one of the samples indicated that the Thai genotype IB strain should be classified in a unique phylogenetic cluster. The analysis using an adjusted odds ratio showed that the consumption of groundwater was the most likely risk factor associated with the disease.

Estimating the critical immunity threshold for preventing hepatitis A outbreaks in men who have sex with men.

Several outbreaks of hepatitis A in men who have sex with men (MSM) were reported in the 1980s and 1990s in Australia and other countries. An effective hepatitis A virus (HAV) vaccine has been available in Australia since 1994 and is recommended for high-risk groups including MSM. No outbreaks of hepatitis A in Australian MSM have been reported since 1996. In this study, we aimed to estimate HAV transmissibility in MSM populations in order to inform targets for vaccine coverage in such populations. We used mathematical models of HAV transmission in a MSM population to estimate the basic reproduction number (R 0) and the probability of an HAV epidemic occurring as a function of the immune proportion. We estimated a plausible range for R 0 of 1·71-3·67 for HAV in MSM and that sustained epidemics cannot occur once the proportion immune to HAV is greater than ~70%. To our knowledge this is the first estimate of R 0 and the critical population immunity threshold for HAV transmission in MSM. As HAV is no longer endemic in Australia or in most other developed countries, vaccination is the only means of maintaining population immunity >70%. Our findings provide impetus to promote HAV vaccination in high-risk groups such as MSM.

Efficacy of domestic cooking inactivation of human hepatitis A virus in experimentally infected manila clams (Ruditapes philippinarum).

AIM: The aim of this work was to evaluate the efficacy of domestic cooking in inactivating Manila clams experimentally infected with human hepatitis A virus (HAV). METHODS AND RESULTS: Electronic temperature probes were positioned to measure the internal temperature of Manila clams during domestic cooking. Two batches were infected with 10(7) and 10(5) TCID50  ml(-1) of HAV. The infected whole-in-shell clams were divided into three replicates and cooked on a conventional stove both singularly and in group and removed from the pan at fixed intervals. Pools of three digestive glands were examined by virus isolation for three blind passages and cell culture supernatant tested with real-time PCR. CONCLUSION: Results showed that 2-min cooking by a traditional domestic method at a temperature close to 100°C, after the opening up of the valves of all the clams, can completely devitalize the HAV in high viral load-infected clams. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study on inactivation of HAV in experimentally infected Manila clams subjected to domestic cooking. At present, labelling all lagoon products as 'requiring cooking before consumption' is highly recommended, but no specifications are given on how long and at what temperature they should be cooked. Considering the high commercial value of Manila clams, our results can provide both the producers and the consumer with useful indications on how to cook clams to prevent the risk of HAV foodborne illness.

[MAVS protein and its interactions with hepatitis A, B and C viruses]. / Bialko MAVS i jego interakcje z wirusami zapalenia watroby typu A, B i C.

Mitochondrial antiviral signaling protein (MAVS) transmits activation signal of type I interferon (IFN) gene transcription in the molecular intracellular pathway, which depends on the protein encoded by retinoic acid inducible gene I (RIG-I) or melanoma differentiation-associated protein-5 (MDA-5). MAVS, as a signal molecule, performs an essential function in the development of an antiviral immune response. The molecule of MAVS consists of two domains: the N-terminal domain and the C-terminal domain. The N-terminal end of MAVS contains the caspase activation and recruitment domain (CARD). CARD is responsible for MAVS interaction with RIG-I and MDA-5, which act as cytosolic sensors detecting foreign viral genetic material in the host cell. After binding to viral RNA, RIG-I or MDA-5 activates MAVS and transmits the signal of IFN type I gene expression. The C-terminal transmembrane domain (TM) of MAVS anchors the protein to the outer mitochondrial membrane. In this paper interactions between MAVS and hepatitis virus type A (HAV), type B (HBV) and type C (HCV) are presented. Mechanisms of indirect activation of MAVS by viral DNA and RNA, as well as the strategies of HAV, HBV and HCV for blocking of the intracellular signaling pathway at the level of MAVS, are described.