Genome Variability and Capsid Structural Constraints of Hepatitis A Virus

Abstract

The number of synonymous mutations per synonymous site (K s ), the number of nonsynonymous mutations per nonsynonymous site (K a ), and the codon usage statistic (N c ) were calculated for several hepatitis A virus (HAV) isolates. While K s was similar to those of poliovirus (PV) and foot-and-mouth disease virus (FMDV), K a was 1 order of magnitude lower. The N c parameter provides information on codon usage bias and decreases when bias increases. The N c value in HAV was about 38, while in PV and FMDV, it was about 53. The emergence of 22 rare codons in front of 8 in PV and 7 in FMDV was detected. Most of the conserved rare codons of the P1 region were strategically located at the carboxy borders of ␤ barrels and ␣ helices, their potential function being the assurance of proper folding of the capsid proteins through a decrease in the translation speed. This strategic location was not observed for amino acids encoded by the conserved rare codons of the 3D region. The percentage of bases with low pairing number values was higher in the latter region, suggesting a role of the conserved rare codons in the maintenance of RNA structure. Many of the rare codons in HAV are among the most frequent in humans, unlike in PV or in FMDV. This fact may be explained by the lack of cellular shutoff in HAV. One hypothesis is that HAV has evolved in order to avoid competition with its host for cellular tRNAs.The high degree of conservation of the amino acid sequences of the capsid proteins of hepatitis A virus (HAV) correlates with a lack of antigenic diversity; thus, there is only a single serotype of human HAV. However, despite this limited amino acid heterogeneity, a significant degree of nucleic acid variability has been observed among different isolates from different regions of the world (3,8,23,25). The molecular bases of this genetic variability may be the high error rate of the viral RNA-dependent RNA polymerase and the absence of proofreading mechanisms. Although no data exist on the error rate of the HAV polymerase, the mutation frequencies for a variety of different RNA viruses range from 10 Ϫ4 to 10 Ϫ5 substitution per base per round of copying (9). The reason why this nucleic acid heterogeneity does not correspond to amino acid heterogeneity should rely on the lack of nonsynonymous mutations, possibly due to their elimination by negative selection. However, the actual mode of transmission of very small HAV populations, frequently associated with contaminated foods, may lead to the accumulation of debilitating mutations (7). In this context, the strikingly low level of amino acid changes in the capsid region suggests strong structural constraints.In the present work, we undertook an analysis of the nucleotide and amino acid changes in sequences representing the available strains from GenBank and isolates from a food-borne hepatitis A outbreak. Since HAV structural data exist only for the 3C protein (4), structural models for the VP2, VP3, VP1, and 3D proteins have been deduced from actual data for the structural prot...

Modulation of Poliovirus Replicative Fitness in HeLa Cells by Deoptimization of Synonymous Codon Usage in the Capsid Region

“…Ribosomal pausing at nonpreferred codons might impair poliovirus protein synthesis and processing in various ways, such as by amino acid misincorporation (55), by increasing the costs of translational proofreading (9), by frameshifting (18), by premature polypeptide chain termination (55), by degradation of the RNA template (23), and by disruption of the proteolytic processing of the polyprotein (56). On the other hand, it has been suggested that the nonrandom locations of nonpreferred codons between structural elements may facilitate proper folding of the nascent capsid proteins of poliovirus (19) and hepatitis A virus (66). However, we did not detect any major alterations in vivo or in vitro in the synthesis and processing of the viral proteins of the codon replacement viruses.…”

Characteristics of synonymous codon usage bias in the beginning region of West Nile virus

“…In addition to analyzing pathways of virus infection in hosts, examining the overall codon usage for an RNA virus open reading frame (ORF) is useful for estimating the evolutionary processes and genetic features of viruses that respond or adapt to the host cell environment (Bahir et al, 2009;Lobo et al, 2009;Wong et al, 2010;Zhou et al, 2013a,b). Recent progress has been made in measuring viral protein translation at the level of synonymous codon usage bias (Sanchez et al, 2003;Burns et al, 2006;Mueller et al, 2006;Bahir et al, 2009;Wong et al, 2010;Poyry and Jackson, 2011;Zhou et al, 2011); however, the contribution of the WNV coding sequence to replication efficiency remains unclear. Here, we employed a simple method for analyzing synonymous codon usage bias in the beginning region of the WNV coding sequence to evaluate the role of codon usage in regulating WNV polyprotein translation.…”

Scientific Opinion on an update on the present knowledge on the occurrence and control of foodborne viruses

“…HAV is a unique picornavirus with many differences in its molecular biology including both its incapacity to induce the inhibition of the cellular protein synthesis and a highly biased and deoptimized codon usage with respect to the cell (Aragones et al, 2008;Borman et al, 1997;Jackson, 2002;Sanchez et al, 2003b). The final goal of this intriguing strategy seems to be the need for a fine-tuning control of the translation kinetics, particularly at the capsid coding region, and the underlying mechanism is the use of a right combination of common and rare codons to allow a regulated ribosome traffic rate thus ensuring the proper protein folding (Aragones et al, 2008;Aragones et al, 2010;Sanchez et al, 2003b). Capsid folding is critical to warrant a high environmental stability for a virus transmitted through the faecaloral route with long extracorporeal periods.…”