SUMMARY: Human astroviruses (HAtVs) are positive-sense single-stranded RNA viruses that were discovered in 1975. Astroviruses infecting other species, particularly mammalian and avian, were identified and classified into the generaMamastrovirusandAvastrovirus. Through next-generation sequencing, many new astroviruses infecting different species, including humans, have been described, and theAstroviridaefamily shows a high diversity and zoonotic potential. Three divergent groups of HAstVs are recognized: the classic (MAstV 1), HAstV-MLB (MAstV 6), and HAstV-VA/HMO (MAstV 8andMAstV 9) groups. Classic HAstVs contain 8 serotypes and account for 2 to 9% of all acute nonbacterial gastroenteritis in children worldwide. Infections are usually self-limiting but can also spread systemically and cause severe infections in immunocompromised patients. The other groups have also been identified in children with gastroenteritis, but extraintestinal pathologies have been suggested for them as well. Classic HAstVs may be grown in cells, allowing the study of their cell cycle, which is similar to that of caliciviruses. The continuous emergence of new astroviruses with a potential zoonotic transmission highlights the need to gain insights on their biology in order to prevent future health threats. This review focuses on the basic virology, pathogenesis, host response, epidemiology, diagnostic assays, and prevention strategies for HAstVs.

Since they were identified in 1975, human astroviruses have been considered one of the most important agents of viral acute gastroenteritis in children. However, highly divergent astroviruses infecting humans have been recently discovered and associated with extra-intestinal infections. The report of cases of fatal meningitis and encephalitis, especially in immunocompromised individuals, has broadened their disease spectrum. Although zoonotic transmission among animal and human astroviruses has not been clearly recognized, the genetic similarity between some human and animal viruses makes it likely to occur. This review provides an update on the epidemiology of both classic and novel human astroviruses, and a comprehensive view on confirmed or potential association between astrovirus and human disease.

A 3-year study involving 2,347 gastroenteritis samples was conducted to determine the prevalence, time distribution, and medical significance of human astrovirus infection in Barcelona, Spain. The overall incidence of astrovirus was found to be 4.9%. Mixed infections with other enteric agents were detected in 17.2% of all astrovirus-positive samples. During the 3-year period, the highest astrovirus incidence was reported in the winter months, although infections also occurred in summer. The peak detection rate was observed in children between 2 and 4 years of age. Overall, HAstV-1 was the most prevalent type, followed by HAstV-4, HAstV-3, HAstV-8, and HAstV-2. HAstV-5, HAstV-6, and HAstV-7 were not detected during these 3 years. From our serotype data for each age group, we observed that HAstV-1, HAstV-2, and HAstV-3 affected mostly children younger than 3 years of age, while HAstV-4 and HAstV-8 had a greater impact in older children. Genetic variability was analyzed between astroviruses isolated in Barcelona and strains isolated in other parts of the world. A fourth lineage was described for HAstV-1, most likely due to the large number of assayed samples, which may also explain the high level of genetic variability observed in the astrovirus isolates.

One hundred eighty-four serologically confirmed cases of hepatitis A were reported in eastern Spain in 1999. A matched case-control study implicated imported coquina clams complying with European Union shellfish standards as the source of infection; this implication was confirmed by the detection by reverse transcription-PCR of hepatitis A virus (HAV) RNA in shellfish samples. In spite of the recognized low variability of HAV, genetic characterization of the complete capsid region of virus isolates from patient serum samples revealed the existence of both synonymous and nonsynonymous variants. Two antigenic variants were detected, one in a discontinuous epitope defined by monoclonal antibody K3-4C8 and a second in a linear VP1 epitope of the virus. In spite of these antigenic variants, all isolates were assigned to genotype IB, providing further evidence that the outbreak originated from a common source, although multiple strains were likely to be involved.

Hepatitis A virus (HAV), the prototype of genus Hepatovirus, has several unique biological characteristics that distinguish it from other members of the Picornaviridae family. Among these, the need for an intact eIF4G factor for the initiation of translation results in an inability to shut down host protein synthesis by a mechanism similar to that of other picornaviruses. Consequently, HAV must inefficiently compete for the cellular translational machinery and this may explain its poor growth in cell culture. In this context of virus/cell competition, HAV has strategically adopted a naturally highly deoptimized codon usage with respect to that of its cellular host. With the aim to optimize its codon usage the virus was adapted to propagate in cells with impaired protein synthesis, in order to make tRNA pools more available for the virus. A significant loss of fitness was the immediate response to the adaptation process that was, however, later on recovered and more associated to a re-deoptimization rather than to an optimization of the codon usage specifically in the capsid coding region. These results exclude translation selection and instead suggest fine-tuning translation kinetics selection as the underlying mechanism of the codon usage bias in this specific genome region. Additionally, the results provide clear evidence of the Red Queen dynamics of evolution since the virus has very much evolved to re-adapt its codon usage to the environmental cellular changing conditions in order to recover the original fitness. Each organism has a specific codon usage signature. Translational selection i.e., selection for the codon adaptation to the tRNA pools, is one of the driving forces of codon bias. In the virus world, this implies an adjustment of the virus codon usage to that of the host cell. Hepatitis A virus appears as an exception to the rule, with a highly deoptimized codon usage, suggesting that translational selection is not the underlying mechanism of its codon bias. However, since the virus lacks a mechanism of cellular protein synthesis inhibition, the deoptimized codon usage may be envisaged as a hawk (cell) and dove (hepatitis A virus) competition strategy for tRNAs and translational selection as well. To confirm this possibility, we artificially induced cell protein synthesis shut-off, thus increasing the tRNA pool availability for the virus, and we took advantage of the quasispecies dynamics to elucidate changes in its codon usage. Virus adaptation to the drug results in a re-deoptimization of codon usage in the capsid region, suggesting a requirement of a slow translation rate, i.e., a translation kinetic selection, instead of a translational selection associated with an optimization of the codon usage. Translation kinetics control is based on the right combination of codons (common and rare) that allows a regulated ribosome traffic rate ensuring the proper protein folding. Capsid folding is critical for a virus transmitted through the fecal-oral route with long extracorporeal periods.