Chapter 47 : Hepatitis A Virus
Authors: Philip R. Spradling, Annette Martin, Stephen M. Feinstone
Hepatitis A Virus, Page 1 of 2
Hepatitis A is an acute, self-limiting infection of the liver by an enterically transmitted picornavirus, hepatitis A virus (HAV). The genetic diversity of HAV has been investigated by determining the partial genomic nucleotide sequences of numerous human HAV strains recovered from various human or simian sources and geographic areas. Antigenic variants of HAV that resist neutralization by neutralizing monoclonal antibodies have been selected in cell culture by continued passage of cell culture-adapted virus in the presence of these antibodies. The marked effectiveness of universal early childhood vaccination has been described in settings where the prevaccine-era hepatitis A incidence was moderately high. Since the licensure of hepatitis A vaccine and the implementation of a national childhood immunization strategy, hepatitis A rates in the United States have fallen dramatically. Host factors reportedly associated with an increased risk of fulminant hepatitis include old age and underlying chronic liver disease. Prolonged jaundice in hepatitis A, often associated with fever and pruritus, is an indication of cholestatic hepatitis. Therefore, decisions to use vaccine or immune globulin (IG) should take into account the potential for severe manifestations of hepatitis A, including patient age and the presence of chronic liver disease. Screening of contacts for immunity before administering postexposure prophylaxis is not recommended because screening would result in delay.
Citation: Spradling P, Martin A, Feinstone S. 2009. Hepatitis A Virus, p 1083-1108. In Richman D, Whitley R, Hayden F (ed), Clinical Virology, Third Edition. ASM Press, Washington, DC. doi: 10.1128/9781555815981.ch47
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Electron micrographs of HAV. (A) Immunoelectron micrograph of HAV particles from human stool reacted with convalescent-phase serum. The particles are heavily coated with and aggregated by antibody. Both "full" and "empty" particles can be seen. (B) Immunoelectron micrograph showing particles from human stool reacted with a preinfection serum. The 27- to 28-nm particles are nearly devoid of antibody, and some fine structure can be seen.
Medium-resolution image of the structure of the HAV particle as revealed by cryoelectron microscopy. The top of the solid triangle defines a fivefold axis of symmetry of the particle. Five such triangles, centered around the fivefold axis of symmetry, delineate a pentamer assembly subunit (dashed footprint). The mature particle contains 12 pentamers. Image reconstructions show significant surface features but suggest that there is no marked canyon around the fivefold axis of symmetry like that found in other picornaviruses. This unique image of the HAV particle was kindly provided in advance of publication by Holland Cheng, University of California at Davis.
HAV genome organization and polyprotein processing. The positive-strand RNA genome, approximately 7.5 kb in length, contains a single open reading frame (ORF) and 5′ and 3′ NTRs of the indicated lengths (bases [b]). The initiator AUG and terminator UGA codons are indicated. The 5′ NTR is covalently linked to the genome-encoded protein 3B (otherwise termed VPg) and contains a structured IRES that determines the cap-independent mechanism of RNA translation initiation. The ORF encodes a polyprotein that is co- and posttranslationally cleaved by the viral protease 3Cpro (at sites indicated by black triangles), a yet-to-be-identified cellular protease (at the site indicated by a gray arrow), or an unknown proteolytic activity (at the site indicated by a gray diamond) to release the mature structural (dark gray boxes) and nonstructural (white boxes) proteins, as well as intermediate precursors (see also Table 1 ).
HAV replication cycle. (a) The viral particle interacts with a cellular receptor (possibly HAVcr1/TIM1) at the hepatocyte surface and is internalized, and the viral genome is uncoated; (b) the positive-strand RNA genome released in the cell cytoplasm is translated through an IRES-dependent mechanism. The resulting polyprotein is proteolytically processed to generate nonstructural proteins involved in genome replication (2B, 2C, 3AB, and 3Dpol) and the protease (3Cpro), as well as capsid proteins. Translation is likely to occur in close proximity to the membranous web induced by 2BC proteins, where RNA replication takes place. (c) Nonstructural proteins assemble into a membrane-bound replicase complex that initiates the synthesis of a minus-strand RNA intermediate, which is then used as a template to generate multiple copies of positive-strand RNA by 3Dpol. These newly synthesized RNAs can be reengaged into either translation or replication processes or (d) encapsidated to generate viral progeny. (e) Newly assembled particles are released from the infected cells by an as-yet-unidentified mechanism.
World map indicating patterns of endemicity of HAV infection (generalized from available data). (Source: CDC.)
Rate of reported hepatitis A, by age group and year, United States, 1990 to 2006. (Source: National Notifiable Disease Surveillance System.)
Rate of reported hepatitis A, by race /ethnicity, United States, 1990 to 2006. (Source: National Notifiable Disease Surveillance System.)
Rate of hepatitis A by county, United States, 1987 to 1997 and 2006. (Source: National Notifiable Disease Surveillance System.)
Experimental inoculation of marmosets (closed markers) and chimpanzees (open markers) with two strains of HAV, HM175 (circles) and MS-1 (squares), showing the inverse relationship between dose and incubation period. (From reference 129 with permission.)
Clinical, virologic, and serologic events after HAV infection. (Source: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_a/slide_1.htm.)
Photomicrograph of a liver biopsy sample taken from an aotus monkey during acute hepatitis A. There is a portal tract infiltration of mononuclear cell, primarily lymphocytes. Some of the inflammatory cells disrupt the limiting plate and extend into the lobule. Magnification, ×193. (Courtesy of Ludmila Asher, Walter Reed Army Institute of Research.)
Electron micrographs of a marmoset hepatocyte during acute hepatitis A. The arrows in the upper panel point to cytoplasmic vesicles containing HAV. The lower panel is a higher-power view of one of the vesicles clearly showing the HAV particles. Bars, 500 nm in the upper panel and 100 nm in the lower. (Reprinted from reference 139 with permission.)
Biphasic enzyme elevation in a tamarin inoculated with 108 infectious units of HAV. There is mild pathology at the time of the first enzyme elevation. The second enzyme elevation begins at about the time of the appearance of serum antibody, and the liver pathology (PATHOL.) is more pronounced than during the first elevation. ICD, isocitric dehydrogenase; HA Ag, HAV antigen (measured by radioimmunoassay [RIA]); im.fl., immunofluorescence.
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HAV structural and regulatory proteins
Recommended doses of IG for hepatitis A preexposure and postexposure prophylaxis a
Recommended schedule for vaccines to prevent hepatitis A a,b
Dosage intervals a,b
Summary of updated recommendations for prevention of hepatitis A after exposure to HAV and in departing international travelers
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