Pathogenicity and virulence of hepatitis A virus

Abstract

Hepatitis A is an acute infection of the liver, which is mostly asymptomatic in children and increases the severity with age. Although in most patients the infection resolves completely, in a few of them it may follow a prolonged or relapsed course or even a fulminant form. The reason for these different outcomes is unknown, but it is generally accepted that host factors such as the immunological status, age and the occurrence of underlaying hepatic diseases are the main determinants of the severity. However, it cannot be ruled out that some virus traits may also contribute to the severe clinical outcomes. In this review, we will analyze which genetic determinants of the virus may determine virulence, in the context of a paradigmatic virus in terms of its genomic, molecular, replicative, and evolutionary features.

Keywords: CpG; HAV; IRES; codon usage; genomic composition; naked virions; quasi-enveloped virions.

Figure 1.

Codon usage-driven capsid folding. The occurrence of clusters of rare codons induce ribosome stallings which slowdown the translation speed. The codon composition of the HAV capsid coding region ensures a fine-tuned translation which results in a low production of highly cohesive capsids. Changes in codon composition increasing the rate of translation result in higher production of otherwise less cohesive capsids. HAV represents an example of the codon usage code for protein structure. Modified from [32]

Figure 2.

HAV exists in a dual phenotype. (a) Naked virions are shed in the feces of infected patients and are responsible for the fecal host-to-host transmission (b). Quasi-enveloped virions are present in the blood and are responsible for the cell-to cell transmission and occasionally parenteral host-to-host transmission. These images were obtained in our lab from supernatants of HuH7 cells infected with the HM175-43 c strain of HAV

Figure 3.

Virulence-transmission trade-off in the context of the HAV singularity. Left cartoon. HAV is transmitted through the fecal-oral route. During the host-to-host transmission, the virions shed in feces may persist for long periods in the environment. The high stability of the naked particles is achieved by the folding acquired through the codon usage-driven slow translation, which in combination with a very inefficient IRES results in low replication. The low virus production and the limited IFN response ends up in a moderate virulence (yellow body). Right cartoon. Changes inducing a faster replication, for instance through epistatic mutations increasing the IRES activity and optimizing the codon composition, may alter the silent dynamics of the HAV cycle increasing its virulence (purple body), and decreasing its host-to-host transmission despite a higher virus production

Figure 4.

Predicted secondary structures of the HAV IRES. Three mutations (blue circles) induce significant structure differences in the IRES from a slow-growing strain (a) and a fast-growing strain (b). The second polypyrimidine tract which precedes the AUG is shown in red. Extracted from [93]