Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention

doi:10.1016/j.jhep.2017.08.034

Journal of Hepatology

Volume 68, Issue 1, January 2018, Pages 167-184

https://doi.org/10.1016/j.jhep.2017.08.034 Get rights and content

Summary

Although epidemic jaundice was well known to physicians of antiquity, it is only in recent years that medical science has begun to unravel the origins of hepatitis A virus (HAV) and the unique pathobiology underlying acute hepatitis A in humans. Improvements in sanitation and the successful development of highly efficacious vaccines have markedly reduced the worldwide occurence of this enterically-transmitted infection over the past quarter century, yet the virus persists in vulnerable populations and those without HAV immunity and remains a common cause of food-borne disease outbreaks in economically-advantaged societies. Reductions in HAV incidence have led to increases in the median age at which infection occurs, often resulting in more severe disease in affected persons and paradoxical increases in disease burden in some developing nations. Here, we summarize recent advances in the molecular virology and epidemiology of HAV, an atypical member of the Picornaviridae family, survey what is known of the pathogenesis of hepatitis A in humans and the host-pathogen interactions that typify the infection. The article also reviews medical and public health aspects of HAV vaccination and disease prevention.

Introduction

Hepatitis A is an ancient disease that has likely afflicted mankind since humans first began to live in groups large enough to sustain transmission of the causative agent, hepatitis A virus (HAV). In reviewing what was known as ‘catarrhal jaundice’ in 1912, Cockayne noted descriptions of epidemic jaundice extending back to antiquity.¹ The infectious nature of the disease was proven several decades later in deliberate human transmission studies.² Such experiments led to a clear distinction between hepatitis A (‘infectious hepatitis’) and hepatitis B (‘homologous serum jaundice’) and recognition of the lack of cross immunity between these two forms of transmissible hepatitis by as early as 1945.³ However, the responsible virus was not identified until almost 30 years later, when small, round viral particles were discovered by immune electron microscopy in the faeces of an experimentally infected human subject by Feinstone et al. in 1973.⁴ This review provides an up-to-date and in-depth overview of HAV and the acute inflammatory hepatic infection it causes in humans, including recently recognised aspects of its molecular virology, evolution, natural history, pathogenesis, epidemiology and prevention.

Section snippets

Genome organisation and virion structure

The molecular cloning of the RNA genome of HAV in the early 1980s revealed its organisation to be similar to the genomes of poliovirus and other viruses classified within the family Picornaviridae.[5], [6] HAV is now classified taxonomically within a unique picornaviral genus, the genus Hepatovirus, which includes only human HAV and other closely related mammalian viruses.⁷ Its single-stranded, positive-sense RNA genome is approximately 7.5 kb in length, with a lengthy 5′ untranslated RNA (UTR)

Animal models of hepatitis A

In addition to humans, chimpanzees (Pan troglodytes), and several small non-human primates are susceptible to HAV.[43], [44], [45], [46] Infection has also been achieved recently by intravenous inoculation of mice genetically deficient either for Ifnar1, a key component of the type I interferon receptor, or for signalling molecules (mitochondrial antiviral signalling [Mavs] or interferon regulatory factors [Irf3/Irf7) involved in the induction of interferon responses to viral infection.³⁸

The epidemiology of HAV

An estimated 1.5 million people are infected annually with HAV.⁷³ This figure is most probably an underestimate because of the asymptomatic presentation of hepatitis A and the limitations regarding epidemiologic information on HAV. Infection with HAV occurs via person-to-person contact and is mainly acquired through faecal-oral transmission resulting from exposure to contaminated water and food. HAV is relatively resistant to freezing, to low pH and to inactivation by moderate heating, as well

Natural history of HAV and its clinical manifestations

Acute HAV infection causes an acute necro-inflammatory process in the liver that normally resolves spontaneously without chronic sequelae. The incubation period of hepatitis A is usually 14–28 days (up to 50 days). Symptoms of hepatitis A range from mild to severe, and can include fever, malaise, fatigue, loss-of-appetite, diarrhoea, nausea, abdominal discomfort, anorexia, myalgia, arthralgia, headache, dark-coloured urine and jaundice.¹¹⁵

Symptoms of HAV infection range from mild to severe and

Current strategies for control and prevention of hepatitis A

Hepatitis A is a vaccine-preventable disease. Protection against HAV infection is afforded by: i) Adequate sanitation and housing facilities, as well as personal hygiene; ii) pre- and post-exposure passive prophylaxis with immune globulin (IG), or iii) pre- or post-exposure active immunisation with an HAV vaccine.

Conclusion

HAV is an ancient virus that has long afflicted human populations. Recent virologic studies have shed new light on the structure, evolution, molecular virology, and pathobiology of this unusual Picornavirus that exists in both quasi-enveloped and naked, non-enveloped infectious forms. Despite development of highly efficacious and safe hepatitis A vaccines, which have been available for more than 20 years, hepatitis A remains a frequent and debilitating disease affecting millions of individuals

Financial support

This work was supported in part by grants from the U.S. National Institutes of Health (R01 AI103083 and R01 AI131685) to S.M. Lemon; J.J. Ott, D. Shouval, and P. Van Damme received no financial support.

Conflict of interest

S.M. Lemon, J.J. Ott and D. Shouval declare no conflict of interest. P. Van Damme acts as principal investigator for vaccine trials conducted on behalf of the University of Antwerp, for which the University obtains research grants from vaccine manufacturers; speaker’s fees for presentations on vaccines are paid directly to an educational fund held by the University of Antwerp. P. Van Damme receives no personal remuneration for this work.

Acknowledgement

We would like to thank Joël Walicki for providing professional assistance with editing references and formatting issues.

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^†: These authors contributed equally.

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SeminarType A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention

Summary

Introduction

Section snippets

Genome organisation and virion structure

Animal models of hepatitis A

The epidemiology of HAV

Natural history of HAV and its clinical manifestations

Current strategies for control and prevention of hepatitis A

Conclusion

Financial support

Conflict of interest

Acknowledgement

Virology

Virology

J Biol Chem

J Biol Chem

Virology

Curr Opin Virol

Infect Genet Evol

Vaccine

Lancet Infect Dis

Vaccine

Vaccine

Vaccine

Catarrhal jaundice, sporadic and epidemic, and its relation to acute yellow atrophy of the liver

Q J Med

Hepatitis A: old and new

Clin Microbiol Rev

Experiment in cross immunity between infectious hepatitis and homologous serum jaundice

Proc Soc Exp Biol Med

Hepatitis A: detection by immune electron microscopy of a viruslike antigen associated with acute illness

Science

Primary structure and gene organization of human hepatitis A virus

Proc Natl Acad Sci U S A

Molecular cloning and characterization of hepatitis A virus cDNA

Proc Natl Acad Sci U S A

The 5′ nontranslated region of hepatitis A virus: secondary structure and elements required for translation in vitro

J Virol

Large deletion mutations involving the first pyrimidine-rich tract of the 5′ nontranslated RNA of hepatitis A virus define two adjacent domains associated with distinct replication phenotypes

J Virol

A hepatitis A virus deletion mutant which lacks the first pyrimidine-rich tract of the 5′ nontranslated RNA remains virulent in primates after direct intrahepatic nucleic acid transfection

J Virol

Identification of a conserved RNA replication element (cre) within the 3Dpol-coding sequence of hepatoviruses

J Virol

Hepatitis A virus cDNA and its RNA transcripts are infectious in cell culture

J Virol

Hepatitis A virus and the origins of picornaviruses

Nature

Antigenic relatedness of two strains of hepatitis A virus determined by cross-neutralization

Infect Immun

Evolutionary origins of hepatitis A virus in small mammals

Proc Natl Acad Sci U S A

A pathogenic picornavirus acquires an envelope by hijacking cellular membranes

Nature

The molecular biology of hepatitis A virus

Hepatitis A virus

Novel perspectives for hepatitis A virus therapy revealed by comparative analysis of hepatitis C virus and hepatitis A virus RNA replication

Hepatology

Interaction of poly(rC) binding protein 2 with the 5′ noncoding region of hepatitis A virus RNA and its effects on translation

J Virol

Antigenic and genetic variation in cytopathic hepatitis A virus variants arising during persistent infection: evidence for genetic recombination

J Virol

Antigenic and immunogenic properties of recombinant hepatitis A virus 14S and 70S subviral particles

J Virol

Acid stability of hepatitis A virus

J Gen Virol

Stability of hepatitis A virus

Intervirology

A novel hepatovirus identified in wild woodchuck Marmota himalayana

Sci Rep

Discovery of a novel hepatovirus (Phopivirus of Seals) related to human hepatitis A virus

mBio

Naked viruses that aren’t always naked: Quasi-enveloped agents of acute hepatitis

Annu Rev Virol

Exosome secretion: molecular mechanisms and roles in immune responses

Traffic

ESCRTs are everywhere

EMBO J

Proline-rich regions and motifs in trafficking: from ESCRT interaction to viral exploitation

Seminar
Type A viral hepatitis: A summary and update on the molecular virology, epidemiology, pathogenesis and prevention