Hepatitis A Virus- An Overview

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Structure of Hepatitis A Virus

  • HAV (Hepatitis A Virus) is a distinct member of the picornavirus family, assigned to genus hepatovirus.
  • HAV is a 27 nm to 32 nm spherical particle with icosahedral symmetry containing a linear single-stranded RNA genome with a size of 7.5 kb and non-enveloped.
Structure of Hepatitis A Virus
Source: Dr. J. H. Hoofnagle and of Abbot Laboratories, Diagnostic Division, North Chicago, Illinois.
  • Hepatitis A virions have a primary buoyant density of 1.32 to 1.34 g/cc in CsCl and a sedimentation coefficient of 156S to 160S in neutral sucrose solutions.

Genome of Hepatitis A Virus

  • HAV can be divided into three parts
    • a 5′ noncoding region (NCR) that comprises approximately 10% of the genome, is uncapped, and is covalently linked at the 5′ terminus to viral protein VPg
    • a single open reading frame that appears to encode all of the viral proteins, with regions designated as P1 for capsid proteins and P2 and P3 for nonstructural proteins
    • a short 3′ NCR terminating in a polyA tail.
Genome of Hepatitis A Virus
Source: A Totsuka, Y Moritsugu, 1999. Hepatitis A virus proteins. Intervirology 426368.
  • The regions P1 contains four segments for structural proteins which make up the capsid protein; 1A-VP4, 1B- VP2, 1C-VP3, 1D-VP1.
  • P2 comprises of three non structural proteins; 2A, 2B, 2C which play a role in viral replication.
  • P3 makes up four non structural proteins
    • 3A- anchors the replication complex to cell membrane
    • 3B- it is VPg protein
    • 3C- it is cysteine protease that cleaves the protein from polypeptides
    • 3D- it is RNA dependent RNA Polymerase.

Epidemiology of Hepatitis A Virus

Epidemiology of Hepatitis A Virus
Source: http://virology-online.com/viruses/HepatitisA.htm
  • Hepatitis A occurs throughout the world.
  • It is highly endemic in some areas, particularly Central and South America, Africa, the Middle East, Asia, and the Western Pacific.

Transmission of Hepatitis A Virus

  • Transmission via fecal-oral route; ingestion of fecally contaminated food (eating uncooked shellfish harvested from sewage) or contaminated water.

Replication of Hepatitis A Virus

Replication of Hepatitis A Virus
Source: Kanda T et al. Direct-acting Antivirals and Host-targeting Agents against the Hepatitis A Virus. J Clin Transl Hepatol. 2015 Sep 28;3(3):205-10. doi: 10.14218/JCTH.2015.00016. Epub 2015 Sep 15.
  • HAV is spread primarily through the ingestion of fecally contaminated food or water.
  • Once HAV reaches the intestine, it is thought to be absorbed into the bloodstream and to reach the liver through the portal system.
  • Attachment of the virus to host cell receptors (HAV cr-1) mediates endocytosis of the virus into the host cell possibly by clathrin- dependent endocytosis.
  • Upon endosomal acidification, the capsid undergoes a conformational change and release VP4 that opens a pore in the host endosomal membrane and the viral genomic RNA penetrates into the host cell cytoplasm.
  • VPg protein is removed from the viral RNA, which is translated into a processed polyproten.
  • The IRES allows direct translation of the polyprotein.
  • A ds RNA genome is synthesized from the genomic ssRNA(+).
  • The dsRNA genome is transcribed thereby providing viral mRNAs/new ssRNA(+) genomes.
  • New genomic RNA is believed to be packaged into preassembled procapsids.
  • Cell lysis occurs and virus is released.

Pathogenesis of Hepatitis A Virus

  • Viral replication occurs primarily within hepatocytes and the secretion of virus into bile results in large quantities of virus being shed in the faeces.
  • During the incubation period, viremia is observed at about the same time that fecal shedding of HAV is occurring.
  • Viremia terminates shortly after hepatitis develops, whereas feces may remain infectious for another 1 to 2 weeks.
  • Acute hepatitis includes features like inflammatory cell infiltration, hepatocellualr necrosis and liver cell regeneration.
  • Portal infiltration by lymphocytes, plasma cells and periodic acid Schiff (PAS)-positive macrophages are prominent features in early biopsies.
  • Parenchymal cells undergo ballooning degeneration.
  • These hepatocytes are swollen and have indistinct plasma membranes, enlarged nuclei, and a featureless cytoplasm, except for some cytoplasmic remnants condensed around the nuclei.
  • Disruption of bile canaliculi may lead to bile retention after liver cell enlargement or necrosis.
  • In some cases, extension of the inflammatory infiltrate from the periportal region into the hepatic parenchyma with significant erosion of the limiting plate is seen.
  • HAV replication in the liver triggers a substantial immune response, both humoral and cell mediated.
  • CD8 +, cytotoxic T cells that are capable of lysing autologous HAV infected cells , but not of controlling uninfected cells, are present both in circulation and in the liver at the site of disease.
  • These virus specific T cells also produce interferon gamma and other cytokines at the site of infection that may be responsible for much of liver injury.
  • In addition to cell mediated immune response, there is vigorous antibody response to the virus during later stages of infection which are directed against conformational epitopes.
  • Neutralizing antiviral antibodies play an important role in clearance of the virus.
  • Serum antibody responses are first noted at onset of symptoms and include virus specific IgM as well as IgG and IgA.

Clinical Manifestations of Hepatitis A Virus

Clinical Manifestations of Hepatitis A Virus
Source: http://www.medicalindiatourism.com/
  • HAV causes an acute, self limiting infection that does not progress to chronic phase.
  • Following exposure, an incubation period of 15-45 days precedes the development of clinical symptoms.
  • Virus is present in blood and shed in stools within a few days of exposure.
  • Symptoms typically occurs abruptly, with liver injury heralded by fever, myalgia, nausea, anorexia and vomiting accompanied by right upper quadrant abdominal pain.
  • Disruption of hepatobilary metabolism results in passage of dark coca cola like urine, light gray coloured stool and frank icterus.
  • Appearance of biochemical abnormalities including abnormal elevation of liver derived enzymes like ALT- alanine aminotransferase, ALP- alkaline phosphatase, GGTP- gamma glutamyl transpeptidase and increased level of serum bilirubin.
  • The severity of infection is associated with age of patient indicating individuals over 50 years of age at increased risk.
  • They may developed fulminant hepatitis with clinical pictures including ascites, bleeding diathesis or hepatic coma.
  • Severe complication includes cholestatic hepatitis characterized by persistent jaundice associated with pruritis, anorexia and weight loss.

Lab Diagnosis of Hepatitis A Virus

Sample: blood, stool, bile, liver biopsy, serum

  1. Antigen detection
  • Detection using PCR and nucleic acid hybridization assay.
  1. Antibody detection
  • Demonstration of IgM antibodies to the virus, which are almost always present at the onset of symptoms and which persist for up to 6 months following infection.
  • IgG antibody usually persists for many years and is a useful indicator of immunity.
  • Antibody detection done by Enzyme linked immunsorbent assay (ELISA).
  1. Liver function test- detection of level of liver enzymes like ALT, ALP, GGTP, and serum bilirubin.

Treatment of Hepatitis A Virus

  • Supportive treatment to reduce other non specific symptoms
  • No antiviral therapy

Vaccination of Hepatitis A Virus

  • Inactivate or live attenuated vaccine confers 90% of prevention.
  • Formalin inactivated HAV vaccine given in two doses- an initial dose followed by booster dose after 6-12 months.
  • Two inactivated whole-virus hepatitis A vaccines are available: HAVRIX (GlaxoSmithKline) and VAQTA (Merck).

Prevention and control of Hepatitis A Virus

  • Persons exposed to HAV (e.g., those who have been served food by an HAV-infected food handler) can be offered administration of serum immune globulin.
  • If given soon after HAV exposure, the anti-HAV antibodies in serum immune globulin can prevent HAV infection or reduce its extent and severity.
  • This form of preventive intervention is known as postexposure prophylaxis.
  • Personnel hygiene and sanitation should be followed.

About Author

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Sagar Aryal

Sagar Aryal is a microbiologist and a scientific blogger. He is doing his Ph.D. at the Central Department of Microbiology, Tribhuvan University, Kathmandu, Nepal. He was awarded the DAAD Research Grant to conduct part of his Ph.D. research work for two years (2019-2021) at Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Saarbrucken, Germany. Sagar is interested in research on actinobacteria, myxobacteria, and natural products. He is the Research Head of the Department of Natural Products, Kathmandu Research Institute for Biological Sciences (KRIBS), Lalitpur, Nepal. Sagar has more than ten years of experience in blogging, content writing, and SEO. Sagar was awarded the SfAM Communications Award 2015: Professional Communicator Category from the Society for Applied Microbiology (Now: Applied Microbiology International), Cambridge, United Kingdom (UK). Sagar is also the ASM Young Ambassador to Nepal for the American Society for Microbiology since 2023 onwards.

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