Hepatology Snapshot:

Hepatitis A: Current view of an ancient disease

Stanley M. Lemon1,*
1
Lineberger Comprehensive Cancer Center, Division of Infectious Diseases, Department of Medicine, and Department of Microbiology & Immunology,
The University of North Carolina at Chapel Hill, USA.
*Corresponding author. Address: Lineberger Comprehensive Cancer Center, Division of Infectious Diseases, Department of Medicine, and Department of Microbiology & Immunology,
The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
E-mail address: smlemon@med.unc.edu

Worldwide epidemiology Genome organization and phylogeny

VP4 pX 3A 3B (VPg)
VP2 VP3 VP1 2B 2C 3Cpro 3Dpol
IRES
Helicase Protease RdRp
VPg AAAAA

7.5 kb (+)-sense RNA genome

U.S. 2016-21
Community outbreaks
27,000 hospitalized
420 deaths Sequence
phylogeny[3]
50% of persons
infected before
5 years of age[2]
Age by which Enteroviruses
50% of persons
are seropositive Cardioviruses
<5
5–10 Insect viruses
10–20
20–40
Aphthoviruses
>40
Fecal-oral and rare parenteral transmission
HAV
Endemic spread, childhood infection in developing regions.
Sporadic community and multi-national outbreaks among
homeless persons and MSM in well-developed nations.
Structural phylogeny[4]

Life cycle
[6]
Quasi-enveloped virus Fecally shed virus is produced in hepatocytes. Bile
acids strip membranes from virus during passage
through the biliary track, resulting in shedding of
highly stable, naked virus
optimized for transmission. [7]
eHAV

Space of Disse
Naked virus
Blood Sinusoid
nHAV

HAV capsids interact with ESCRT-related

proteins, bud into multi-vesicular endosomes
(MVE), and are released from hepatocytes
wrapped in membranes. eHAV is resistant to
neutralizing antibodies, providing for stealthy
virus spread in vivo.[6] Endosomal Hepatocyte
gangliosides (GD1a) bind virus and are
essential for viral entry into uninfected cells.[8]
Bile flow

Hepatitis A in interferon-receptor knockout (Ifnar1-/-) mice Hepatitis A vaccine

Formalin-inactivated virus from cell culture[14]

Safe and highly immunogenic
Pre-exposure and post-exposure prophylaxis
106 Feces GE/10 mg 250 Modeling predicts life-long protection
Serum GE/10 μl

200
105 Observed
105
HAV RNA

150 Predicted
ALT (IU/L)

GMT anti-HAV antibody

4
10
100
104
(mIU/ml)

103
50

Cleaved caspase 3
ND ND 102
<103 0
8 14 21 28 35 14 Level of protective antibody = 10 mIU/ml
Days post-inoculation 101

IRF3-dependent apoptosis[9] 4 weeks 5-6 10 20 30 40 50

Virus-specific CD8+ T cells limit liver injury[11] postdose Years following two-dose schedule
2 (25U Vaqta®) in childhood
Hepatocellular apoptosis 2.5-3.5

In humans: non-specific CD8+ “bystander” T cell activation[12] Years following two-dose schedule in childhood[13]

Keywords: Hepatovirus; picornavirus, quasi-enveloped virus; pathogenesis; transmission; animal model; liver injury; viral entry.
See the online version for the full list of references.
Received 11 May 2021; received in revised form 09 September 2021; accepted 19 September 2021. Journal of Hepatology 2022 vol. 77 | 243--244
Hepatology Snapshot
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 wide-
spread 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 crystal-
lographic 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 he-
patocytes 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-envelop-
ment 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 al-
ways acute and rarely if ever persists more than 6 months. Cardinal
features include hepatocellular apoptosis, multi-cellular intra-
hepatic inflammatory infiltrates, and elevated serum alanine
aminotransferase activities. Multiple mechanisms likely contribute
to pathogenesis. Ifnar1-/- mice deficient in type I interferon re-
ceptors 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-
Journal of Hepatology 2022 vol. 77 j 243–244
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-expo-
sure 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 In-
fectious 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
Supplementary data to this article can be found online at https://
doi.org/10.1016/j.jhep.2021.09.028.
References
Author names in bold designate shared co-first authorship
[1] Lemon SM, Ott JJ, Van Damme P, Shouval D. Type A viral hepatitis: a
summary and update on the molecular virology, epidemiology, patho-
genesis and prevention. J Hepatol 2018;68:167–184.
[2] Jacobsen KH. Globalization and the changing epidemiology of hepatitis A
virus. Cold Spring Harb Perspect Med 2018;8:a031716.
[3] Sander AL, Corman VM, Lukashev AN, Drexler JF. Evolutionary origins of
enteric hepatitis viruses. Cold Spring Harb Perspect Med 2018;8:a031690.
[4] Wang X, Ren J, Gao Q, Hu Z, Sun Y, Li X, et al. Hepatitis A virus and the
origins of picornaviruses. Nature 2015;517:85–88.
[5] Lanford RE, Feng Z, Chavez D, Guerra B, Brasky KM, Zhou Y, et al. 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.
[6] Feng Z, Hensley L, McKnight KL, Hu F, Madden V, Ping L, et al.
A pathogenic picornavirus acquires an envelope by hijacking cellular
membranes. Nature 2013;496:367–371.
[7] Hirai-Yuki A, Hensley L, Whitmire JK, Lemon SM. Biliary secretion of
quasi-enveloped human hepatitis A virus. MBio 2016;7. e01998-01916.
[8] Das A, Barrientos RC, Shiota T, Madigan V, Misumi I, McKnight KL, et al.
Gangliosides are essential endosomal receptors for quasi-enveloped and
naked hepatitis A virus. Nat Microbiol 2020;5:1069–1078.
[9] Hirai-Yuki A, Hensley L, McGivern DR, Gonzalez-Lopez O, Das A, Feng H,
et al. MAVS-dependent host species range and pathogenicity of human
hepatitis A virus. Science 2016;353:1541–1545.
[10] Zhou Y, Callendret B, Xu D, Brasky KM, Feng Z, Hensley LL, et al. Domi-
nance of the CD4+ T helper cell response during acute resolving hepatitis
A virus infection. J Exp Med 2012;209:1481–1492.
[11] Misumi I, Mitchell JE, Lund MM, Cullen J, Lemon SM, Whitmire JK. T cells
protect against hepatitis A virus infection and limit infection-induced
liver injury. J Hepatol 2021;75:1323–1334.
[12] Kim J, Chang DY, Lee HW, Lee H, Kim JH, Sung PS, et al. 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.
[13] Martin JC, Petrecz ML, Stek JE, Simon JK, Goveia MG, Klopfer SO. Using the
power law model to predict the long-term persistence and duration of
detectable hepatitis A antibody after receipt of hepatitis A vaccine
(VAQTATM). Vaccine 2021;39:2764–2771.
[14] Volkin DB, Burke CJ, Marfia KE, Oswald CB, Wolanski B, Middaugh CR. Size
and conformational stability of the hepatitis A virus used to prepare
VAQTA, a highly purified inactivated vaccine. J Pharmaceut Sci
1997;86:666–673.