Chapter 24 : Hepatitis A Virus

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The most common clinical manifestation of hepatitis A virus (HAV) infection is acute hepatitis, which typically presents with rapid onset of nausea, loss of appetite, fever, abdominal pain, dark urine, and jaundice. Importantly, HAV causes only acute hepatitis, and long-term persistent infection has never been well documented or clearly associated with chronic liver disease. The internal ribosome entry site (IRES) structure is unique, but overall resembles the aphthovirus IRES more than the enterovirus IRES. Importantly, the HAV IRES is distinguished from other picornaviral IRES elements by its apparent requirement for all eukaryotic translation initiation factors, including intact eIF- 4G, to direct internal entry of the 40S ribosome on the viral RNA. In vivo, the virus is thought to replicate primarily within hepatocytes. The infecting HAV particle presumably arrives at the basolateral membrane surface of the hepatocyte, within the space of Disse, via the portal circulation from the intestines and diffusion through the hepatic sinusoids. Viremia is present throughout much of the incubation period and into the acute phase of illness but is reduced in magnitude (as is the fecal shedding of virus) with the onset of hepatitis and the appearance of antibodies to HAV.

Citation: Feng Z, Lemon S. 2010. Hepatitis A Virus, p 383-396. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch24
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Image of Figure 1.
Figure 1.

Histopathologic abnormalities in the liver of a patient with acute HAV infection. There is extensive inflammation of the portal and periportal areas by lymphocytes and other small, mononuclear cells (upper right field) and moderate loss of the normal hepatic architecture with lobular disarray (lower left field). There is also prominent hepatocellular ballooning degeneration (cytoplasmic vacuolization). Hematoxylin and eosin stain was used. Original magnification, ×40. (Image reproduced with permission of the publisher from Martin and Lemon [ ] and originally provided by S.-Y. Xiao.)

Citation: Feng Z, Lemon S. 2010. Hepatitis A Virus, p 383-396. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch24
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Image of Figure 2.
Figure 2.

Acute HAV infection in a New World owl monkey challenged by intravenous inoculation with 4.10 log focus-forming units of a cell culture-derived but still virulent virus ( ). Viremia ( ), fecal virus shedding ( ), and intrahepatic virus titer ( ) were determined by virus isolation in cell culture. The antibody response to the infection was measured by an isotypenonspecific competitive inhibition immunoassay. After several weeks of intense fecal virus shedding, biochemical evidence of liver injury (ALT elevations) developed simultaneously with the appearance of HAV-specific antibody and termination of virus replication.

Citation: Feng Z, Lemon S. 2010. Hepatitis A Virus, p 383-396. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch24
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Image of Figure 3.
Figure 3.

Organization of the ˜7.2-kb HAV genome. The open reading frame is shown as a box, flanked by the 5′ and 3′ UTRs, which contain an IRES and a poly(A) tail, respectively. The sites of polyprotein cleavage occurring during processing are indicated, with the arrow marking the primary cleavage at the 2A-2B junction. Shown below the genome is an expanded view of the structural proteins. All processing events with the exception of the VP0 (VP4-VP2) maturation cleavage ( ) and PX (VP1-2A) cleavage (*) are mediated by 3C, a cysteine protease and the only protease expressed by the virus. The PX cleavage gives rise to mature VP1 protein with heterogenous carboxyl termini, and the reaction is catalyzed by an unknown cellular protease.

Citation: Feng Z, Lemon S. 2010. Hepatitis A Virus, p 383-396. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch24
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Image of Figure 4.
Figure 4.

HAV infection of FRhK-4 cells disrupts signal transduction from RLR pathogen recognition receptors. Cells, either uninfected or infected for 3 days with HM175/18f virus at a multiplicity of infection of 1, were transfected with luciferase reporter plasmids for IFN-β (left panel; IRF-3-responsive) and PRD-II (right panel; NF-κB-responsive) promoter elements and then either mock challenged (open bars) or challenged with Sendai virus (solid bars), a robust agonist of RIG-I-mediated IFN responses. Sendai virus gene expression is not inhibited by HAV infection. (Reproduced from [ ] with permission. Copyright 2007, National Academy of Sciences, USA.)

Citation: Feng Z, Lemon S. 2010. Hepatitis A Virus, p 383-396. In Ehrenfeld E, Domingo E, Roos R (ed), The Picornaviruses. ASM Press, Washington, DC. doi: 10.1128/9781555816698.ch24
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