Review

Authors: Rosa M Pintó, Francisco-Javier Pérez-Rodríguez, Maria-Isabel Costafreda...

Hepatitis A is an acute infection of the liver, which is mostly asymptomatic in children and increases the severity with age. Although in most patients the infection resolves completely, in a few of them it may follow a prolonged or relapsed course or even a fulminant form. The reason for these different outcomes is unknown, but it is generally accepted that host factors such as the immunological status, age and the occurrence of underlaying hepatic diseases are the main determinants of the severity. However, it cannot be ruled out that some virus traits may also contribute to the severe clinical outcomes. In this review, we will analyze which genetic determinants of the virus may determine virulence, in the context of a paradigmatic virus in terms of its genomic, molecular, replicative, and evolutionary features.

Topics: Child; Hepatitis A; Hepatitis A virus; Humans; Virulence

PubMed: 33843464
DOI: 10.1080/21505594.2021.1910442

Review

Authors: Omana V Nainan, Guoliang Xia, Gilberto Vaughan...

Current serologic tests provide the foundation for diagnosis of hepatitis A and hepatitis A virus (HAV) infection. Recent advances in methods to identify and characterize nucleic acid markers of viral infections have provided the foundation for the field of molecular epidemiology and increased our knowledge of the molecular biology and epidemiology of HAV. Although HAV is primarily shed in feces, there is a strong viremic phase during infection which has allowed easy access to virus isolates and the use of molecular markers to determine their genetic relatedness. Molecular epidemiologic studies have provided new information on the types and extent of HAV infection and transmission in the United States. In addition, these new diagnostic methods have provided tools for the rapid detection of food-borne HAV transmission and identification of the potential source of the food contamination.

Topics: Animals; Hepatitis A; Hepatitis A virus; Humans; Molecular Epidemiology

PubMed: 16418523
DOI: 10.1128/CMR.19.1.63-79.2006

Review

Authors: Fausto E L Pereira, Carlos S Gonçalves

Hepatitis A infection is known since the ancient Chinese, Greek and Roman civilizations but the first documented report was published in the eighteenth century. The hepatovirus belongs to the Picornaviridae family, and carries a single strand RNA. There are 7 genotypes. Antibodies of the IgM and IgA classes, during natural infections, appear early in the serum, together with the first clinical manifestations of the disease, but they may also appear at the end of the first week of infection. There is a spectrum of clinical presentation: asymptomatic infection, symptomatic without jaundice and symptomatic jaundiced. A rare fatal form of hepatitis has been described. Diagnosis of the hepatitis A infection is confirmed by the finding of IgM anti-HAV antibodies, routinely performed using an ELISA test. Treatment is supportive. Intramuscular anti-A gamma globulin is used for passive immune prophylaxis, and there is an efficient vaccine for active immune prophylaxis.

Topics: Hepatitis A; Hepatitis A Antibodies; Hepatitis A Vaccines; Hepatitis A virus; Humans

PubMed: 12908041
DOI: 10.1590/s0037-86822003000300012

Review

Authors: Stephanie C Brundage, A Nicole Fitzpatrick

The introduction of hepatitis A vaccines in 1995 led to a drop in the number of reported cases of hepatitis A and a shift to a higher percentage of cases occurring in older age groups. The hepatitis A virus survives for extended periods in the environment. Transmission primarily is fecal-oral, although there have been rare instances of transmission through blood products. The virus appears sporadically and is spread by close personal contact, with occasional food-borne outbreaks. Older persons infected by the virus usually develop a symptomatic infection with abrupt onset, fever, and jaundice lasting two months. Children usually have an asymptomatic infection and rarely develop jaundice. Laboratory diagnosis is made by detection of antihepatitis A virus immunoglobulin M in serum. Ten to 20 percent of symptomatic patients experience a prolonged or relapsing course of illness, but chronic infection has not been reported. Fulminant infection occurs in less than 1 percent of patients and can result in emergent liver transplant or death. Prevention starts with thorough handwashing and careful food handling. Prompt disease reporting, the identification of exposed persons, and expeditious administration of immune globulin prevent secondary transmission of the disease. Physicians should consider routine vaccination of children 12 to 23 months of age based on recommendations from the Centers for Disease Control and Prevention. Vaccination for children two years or older and adults should be included in routine preventive care for those at increased risk of contracting the disease (e.g., travelers to certain countries, men who have sex with men, drug abusers, recipients of clotting factor replacement) and for persons with chronic liver disease.

Topics: Diagnosis, Differential; Hand Disinfection; Hepatitis A; Hepatitis A Vaccines; Hepatovirus; Humans; Immunoglobulins, Intravenous; Liver Failure, Acute; Refuse Disposal; Vaccination

PubMed: 16848078
DOI: No ID Found

Authors: You Li, Ichiro Misumi, Tomoyuki Shiota...

Despite excellent vaccines, resurgent outbreaks of hepatitis A have caused thousands of hospitalizations and hundreds of deaths within the United States in recent years. There is no effective antiviral therapy for hepatitis A, and many aspects of the hepatitis A virus (HAV) replication cycle remain to be elucidated. Replication requires the zinc finger protein ZCCHC14 and noncanonical TENT4 poly(A) polymerases with which it associates, but the underlying mechanism is unknown. Here, we show that ZCCHC14 and TENT4A/B are required for viral RNA synthesis following translation of the viral genome in infected cells. Cross-linking immunoprecipitation sequencing (CLIP-seq) experiments revealed that ZCCHC14 binds a small stem-loop in the HAV 5' untranslated RNA possessing a Smaug recognition-like pentaloop to which it recruits TENT4. TENT4 polymerases lengthen and stabilize the 3' poly(A) tails of some cellular and viral mRNAs, but the chemical inhibition of TENT4A/B with the dihydroquinolizinone RG7834 had no impact on the length of the HAV 3' poly(A) tail, stability of HAV RNA, or cap-independent translation of the viral genome. By contrast, RG7834 inhibited the incorporation of 5-ethynyl uridine into nascent HAV RNA, indicating that TENT4A/B function in viral RNA synthesis. Consistent with potent in vitro antiviral activity against HAV (IC 6.11 nM), orally administered RG7834 completely blocked HAV infection in mice, and sharply reduced serum alanine aminotransferase activities, hepatocyte apoptosis, and intrahepatic inflammatory cell infiltrates in mice with acute hepatitis A. These results reveal requirements for ZCCHC14-TENT4A/B in hepatovirus RNA synthesis, and suggest that TENT4A/B inhibitors may be useful for preventing or treating hepatitis A in humans.

Topics: Animals; Antiviral Agents; Chromosomal Proteins, Non-Histone; DNA-Directed DNA Polymerase; Hepatitis A; Hepatitis A virus; Humans; Intrinsically Disordered Proteins; Mice; Mice, Mutant Strains; RNA Nucleotidyltransferases; RNA, Viral; Receptor, Interferon alpha-beta; Virus Replication

PubMed: 35867748
DOI: 10.1073/pnas.2204511119

Authors: Tomoyuki Shiota, Zhucui Li, Guan-Yuan Chen...

Virus-induced changes in host lipid metabolism are an important but poorly understood aspect of viral pathogenesis. By combining nontargeted lipidomics analyses of infected cells and purified extracellular quasi-enveloped virions with high-throughput RNA sequencing and genetic depletion studies, we show that hepatitis A virus, an hepatotropic picornavirus, broadly manipulates the host cell lipid environment, enhancing synthesis of ceramides and other sphingolipids and transcriptionally activating acyl-coenzyme A synthetases and fatty acid elongases to import and activate long-chain fatty acids for entry into the fatty acid elongation cycle. Phospholipids with very-long-chain acyl tails (>C22) are essential for genome replication, whereas increases in sphingolipids support assembly and release of quasi-enveloped virions wrapped in membranes highly enriched for sphingomyelin and very-long-chain ceramides. Our data provide insight into how a pathogenic virus alters lipid flux in infected hepatocytes and demonstrate a distinction between lipid species required for viral RNA synthesis versus nonlytic quasi-enveloped virus release.

Topics: Hepatovirus; RNA, Viral; RNA Replication; Virus Release; Virus Replication; Fatty Acids; Sphingolipids; Ceramides

PubMed: 37862421
DOI: 10.1126/sciadv.adj4198

Review

Authors:

Topics: Animals; Canada; Disease Outbreaks; Food Contamination; Hepatitis A; Hepatovirus; Humans; Injections; Primates; Time Factors; Transfusion Reaction; gamma-Globulins

PubMed: 4183650
DOI: No ID Found

Review

Authors: Anna-Lena Sander, Victor Max Corman, Alexander N Lukashev...

The enterically transmitted hepatitis A (HAV) and hepatitis E viruses (HEV) are the leading causes of acute viral hepatitis in humans. Despite the discovery of HAV and HEV 40-50 years ago, their evolutionary origins remain unclear. Recent discoveries of numerous nonprimate hepatoviruses and hepeviruses allow revisiting the evolutionary history of these viruses. In this review, we provide detailed phylogenomic analyses of primate and nonprimate hepatoviruses and hepeviruses. We identify conserved and divergent genomic properties and corroborate historical interspecies transmissions by phylogenetic comparisons and recombination analyses. We discuss the likely non-recent origins of human HAV and HEV precursors carried by mammals other than primates, and detail current zoonotic HEV infections. The novel nonprimate hepatoviruses and hepeviruses offer exciting new possibilities for future research focusing on host range and the unique biological properties of HAV and HEV.

Topics: Animals; Disease Reservoirs; Evolution, Molecular; Genotype; Hepatitis A; Hepatitis A Virus, Human; Hepatitis A virus; Hepatitis E; Hepatitis E virus; Humans; Mammals; Phylogeny; Primates; Zoonoses

PubMed: 29610146
DOI: 10.1101/cshperspect.a031690

Review

Authors: David I Stuart, Jingshan Ren, Xiangxi Wang...

Hepatitis A virus (HAV) has been enigmatic, evading detailed structural analysis for many years. Its recently determined high-resolution structure revealed an angular surface without the indentations often characteristic of receptor-binding sites. The viral protein 1 (VP1) β-barrel shows no sign of a pocket factor and the amino terminus of VP2 displays a "domain swap" across the pentamer interface, as in a subset of mammalian picornaviruses and insect picorna-like viruses. Structure-based phylogeny confirms this placement. These differences suggest an uncoating mechanism distinct from that of enteroviruses. An empty capsid structure reveals internal differences in VP0 and the VP1 amino terminus connected with particle maturation. An HAV/Fab complex structure, in which the antigen-binding fragment (Fab) appears to act as a receptor-mimic, clarifies some historical epitope mapping data, but some remain difficult to reconcile. We still have little idea of the structural features of enveloped HAV particles.

Topics: Capsid; Capsid Proteins; Hepatitis A virus; Phylogeny; Picornaviridae; Virion; Virus Internalization; Virus Replication

PubMed: 30037986
DOI: 10.1101/cshperspect.a031807

Authors: Jan Felix Drexler, Victor M Corman, Alexander N Lukashev...

Hepatitis A virus (HAV) is an ancient and ubiquitous human pathogen recovered previously only from primates. The sole species of the genus Hepatovirus, existing in both enveloped and nonenveloped forms, and with a capsid structure intermediate between that of insect viruses and mammalian picornaviruses, HAV is enigmatic in its origins. We conducted a targeted search for hepatoviruses in 15,987 specimens collected from 209 small mammal species globally and discovered highly diversified viruses in bats, rodents, hedgehogs, and shrews, which by pairwise sequence distance comprise 13 novel Hepatovirus species. Near-complete genomes from nine of these species show conservation of unique hepatovirus features, including predicted internal ribosome entry site structure, a truncated VP4 capsid protein lacking N-terminal myristoylation, a carboxyl-terminal pX extension of VP1, VP2 late domains involved in membrane envelopment, and a cis-acting replication element within the 3D(pol) sequence. Antibodies in some bat sera immunoprecipitated and neutralized human HAV, suggesting conservation of critical antigenic determinants. Limited phylogenetic cosegregation among hepatoviruses and their hosts and recombination patterns are indicative of major hepatovirus host shifts in the past. Ancestral state reconstructions suggest a Hepatovirus origin in small insectivorous mammals and a rodent origin of human HAV. Patterns of infection in small mammals mimicked those of human HAV in hepatotropism, fecal shedding, acute nature, and extinction of the virus in a closed host population. The evolutionary conservation of hepatovirus structure and pathogenesis provide novel insight into the origins of HAV and highlight the utility of analyzing animal reservoirs for risk assessment of emerging viruses.

Topics: Animals; Biological Evolution; Hepatitis A virus; Humans; Mammals; Molecular Sequence Data; Phylogeny

PubMed: 26575627
DOI: 10.1073/pnas.1516992112