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Hepatitis A: Current view of an ancient disease

  • Stanley M. Lemon
    Correspondence
    Corresponding author. Address: 8.034 Burnett-Womack Building CB#7292, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7292, USA.
    Affiliations
    Lineberger Comprehensive Cancer Center, Division of Infectious Diseases, Department of Medicine, Department of Microbiology & Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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      Keywords

      Type A viral hepatitis is an enterically transmitted form of acute hepatitis caused by hepatitis A virus (HAV), an atypical, plus-strand RNA virus classified in the genus Hepatovirus within the family Picornaviridae.
      • Lemon S.M.
      • Ott J.J.
      • Van Damme P.
      • Shouval D.
      Type A viral hepatitis: a summary and update on the molecular virology, epidemiology, pathogenesis and prevention.
      An ancient disease, hepatitis A has likely plagued mankind since transition from hunter-gatherer status to communal living in larger settled societies 8,000-10,000 years ago. It remains endemic in under-developed regions, especially sub-Saharan Africa where 50% of children are infected before the age of 5.
      • Jacobsen K.H.
      Globalization and the changing epidemiology of hepatitis A virus.
      Usually well controlled in developed nations by sanitation and vaccines, hepatitis A has re-emerged as a public health threat in recent years with widespread outbreaks among homeless persons in the U.S. and among men who have sex with men (MSM) in Europe.
      HAV was identified in 1973 in feces from prisoner volunteers who were experimentally infected with the virus in the 1960s. Following the licensure of hepatitis A vaccines in the 1990s, research on HAV and hepatitis A entered a period of relative dormancy. Interest in hepatitis A has been rekindled over the past decade, however, as it has become increasingly apparent that HAV is unique in terms of its phylogeny, structure and replication strategy. Nine closely related but distinct hepatovirus species are now recognized, only one of which, Hepatovirus A, infects humans. Other hepatoviruses are found in a variety of mammals (seals, bats, opossums, etc.).
      • Sander A.L.
      • Corman V.M.
      • Lukashev A.N.
      • Drexler J.F.
      Evolutionary origins of enteric hepatitis viruses.
      Interestingly, bat hepatovirus appears to be hepatotropic and antigenically related to human HAV. A crystallographic model of the HAV capsid shows its structure to be distinct from poliovirus and many other human picornaviruses, with features found in picorna-like viruses of insects.
      • Wang X.
      • Ren J.
      • Gao Q.
      • Hu Z.
      • Sun Y.
      • Li X.
      • et al.
      Hepatitis A virus and the origins of picornaviruses.
      Human HAV is noncytopathic and highly hepatotropic, infecting the liver in a stealth-like manner.
      • Lanford R.E.
      • Feng Z.
      • Chavez D.
      • Guerra B.
      • Brasky K.M.
      • Zhou Y.
      • et al.
      Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA.
      It is released from infected hepatocytes in small vesicles lacking any virally encoded protein on their surface.
      • Feng Z.
      • Hensley L.
      • McKnight K.L.
      • Hu F.
      • Madden V.
      • Ping L.
      • et al.
      A pathogenic picornavirus acquires an envelope by hijacking cellular membranes.
      These quasi-enveloped virions (eHAV) resemble exosomes in their biogenesis. They are infectious, and the only form of virus found in blood.
      • Feng Z.
      • Hensley L.
      • McKnight K.L.
      • Hu F.
      • Madden V.
      • Ping L.
      • et al.
      A pathogenic picornavirus acquires an envelope by hijacking cellular membranes.
      Bile salts strip membranes from quasi-enveloped virions released into the biliary tract, resulting in fecal shedding of naked, non-enveloped virus (nHAV).
      • Hirai-Yuki A.
      • Hensley L.
      • Whitmire J.K.
      • Lemon S.M.
      Biliary secretion of quasi-enveloped human hepatitis A virus.
      Quasi-envelopment protects the capsid in eHAV from neutralizing antibodies, and likely promotes stealthy spread of the virus within the liver early in infection. By contrast, naked virus shed in feces is highly stable and optimized for environmental transmission. Both virus types enter newly infected cells via clathrin-dependent endocytosis with endolysosomal gangliosides acting subsequently as receptors mediating entry into the cytoplasm.
      • Das A.
      • Barrientos R.C.
      • Shiota T.
      • Madigan V.
      • Misumi I.
      • McKnight K.L.
      • et al.
      Gangliosides are essential endosomal receptors for quasi-enveloped and naked hepatitis A virus.
      TIM1 (a.k.a. HAVCR1) and other phosphotidylserine receptors facilitate initial attachment of eHAV to cells but are not required for infection.
      Liver injury, which accompanies infection in most adults, is always acute and rarely if ever persists more than 6 months. Cardinal features include hepatocellular apoptosis, multi-cellular intrahepatic inflammatory infiltrates, and elevated serum alanine aminotransferase activities. Multiple mechanisms likely contribute to pathogenesis. Ifnar1-/- mice deficient in type I interferon receptors are permissive for HAV infection and accurately model many aspects of hepatitis A in humans.
      • Hirai-Yuki A.
      • Hensley L.
      • McGivern D.R.
      • Gonzalez-Lopez O.
      • Das A.
      • Feng H.
      • et al.
      MAVS-dependent host species range and pathogenicity of human hepatitis A virus.
      In these mice, liver injury results solely from interferon regulatory factor 3 (IRF3)-mediated transcriptional responses. Such virus-induced IRF3 responses are muted, but not completely ablated, in human cells by HAV protease cleavage of the innate immune signaling molecules, MAVS and TRIF.
      • Lemon S.M.
      • Ott J.J.
      • Van Damme P.
      • Shouval D.
      Type A viral hepatitis: a summary and update on the molecular virology, epidemiology, pathogenesis and prevention.
      Virus-specific CD8+ T cells contribute little to the liver injury associated with HAV infection in chimpanzees,
      • Zhou Y.
      • Callendret B.
      • Xu D.
      • Brasky K.M.
      • Feng Z.
      • Hensley L.L.
      • et al.
      Dominance of the CD4+ T helper cell response during acute resolving hepatitis A virus infection.
      and in fact protect against liver injury in mice.
      • Misumi I.
      • Mitchell J.E.
      • Lund M.M.
      • Cullen J.
      • Lemon S.M.
      • Whitmire J.K.
      T cells protect against hepatitis A virus infection and limit infection-induced liver injury.
      Other mechanisms, particularly non-specific CD8+ bystander T cell activation, may account for severe hepatitis in individuals requiring hospitalization.
      • Kim J.
      • Chang D.Y.
      • Lee H.W.
      • Lee H.
      • Kim J.H.
      • Sung P.S.
      • et al.
      Innate-like cytotoxic function of bystander-activated CD8(+) T Cells is associated with liver injury in acute hepatitis A.
      No specific therapy exists for the treatment of hepatitis A. Inactivated vaccines contain both empty and full HAV capsids produced in cell culture and inactivated with formalin, and are effective in both pre-exposure and post-exposure settings.
      • Lemon S.M.
      • Ott J.J.
      • Van Damme P.
      • Shouval D.
      Type A viral hepatitis: a summary and update on the molecular virology, epidemiology, pathogenesis and prevention.
      Modeling suggests protective antibody responses may persist for 25-50 years following childhood immunization.
      • Martin J.C.
      • Petrecz M.L.
      • Stek J.E.
      • Simon J.K.
      • Goveia M.G.
      • Klopfer S.O.
      Using the power law model to predict the long-term persistence and duration of detectable hepatitis A antibody after receipt of hepatitis A vaccine (VAQTA™).
      ,
      • Volkin D.B.
      • Burke C.J.
      • Marfia K.E.
      • Oswald C.B.
      • Wolanski B.
      • Middaugh C.R.
      Size and conformational stability of the hepatitis A virus used to prepare VAQTA, a highly purified inactivated vaccine.

      Financial support

      Research related to hepatitis A in the author’s laboratory is funded by grants from the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health: R01-AI131685, R01-AI103083, and R01-AI150095.

      Conflict of interest

      The author declares no conflict of interest.
      Please refer to the accompanying ICMJE disclosure form for further details.

      Supplementary data

      The following are the supplementary data to this article:

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