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.
[1]
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.[2]
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.).
[3]
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.[4]
Human HAV is noncytopathic and highly hepatotropic, infecting the liver in a stealth-like manner.
[5]
It is released from infected hepatocytes in small vesicles lacking any virally encoded protein on their surface.[6]
These quasi-enveloped virions (eHAV) resemble exosomes in their biogenesis. They are infectious, and the only form of virus found in blood.[6]
Bile salts strip membranes from quasi-enveloped virions released into the biliary tract, resulting in fecal shedding of naked, non-enveloped virus (nHAV).[7]
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.[8]
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.
[9]
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.[1]
Virus-specific CD8+ T cells contribute little to the liver injury associated with HAV infection in chimpanzees,[10]
and in fact protect against liver injury in mice.[11]
Other mechanisms, particularly non-specific CD8+ bystander T cell activation, may account for severe hepatitis in individuals requiring hospitalization.[12]
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.[1]
Modeling suggests protective antibody responses may persist for 25-50 years following childhood immunization.[13]
,[14]
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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References
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- Hepatitis A virus and the origins of picornaviruses.Nature. 2015; 517: 85-88
- Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA.Proc Nat'l Acad Sci USA. 2011; 108: 11223-11228
- A pathogenic picornavirus acquires an envelope by hijacking cellular membranes.Nature. 2013; 496: 367-371
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- Gangliosides are essential endosomal receptors for quasi-enveloped and naked hepatitis A virus.Nat Microbiol. 2020; 5: 1069-1078
- MAVS-dependent host species range and pathogenicity of human hepatitis A virus.Science. 2016; 353: 1541-1545
- Dominance of the CD4+ T helper cell response during acute resolving hepatitis A virus infection.J Exp Med. 2012; 209: 1481-1492
- T cells protect against hepatitis A virus infection and limit infection-induced liver injury.J Hepatol. 2021; 75: 1323-1334
- Innate-like cytotoxic function of bystander-activated CD8(+) T Cells is associated with liver injury in acute hepatitis A.Immunity. 2018; 48: 161-173.e165
- 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™).Vaccine. 2021; 39: 2764-2771
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Article info
Publication history
Published online: May 02, 2022
Accepted:
September 19,
2021
Received in revised form:
September 9,
2021
Received:
May 11,
2021
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2021 Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
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