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Review
. 2014 Oct;27(4):1048-74.
doi: 10.1128/CMR.00013-14.

Human astroviruses

Albert Bosch  1 , Rosa M Pintó  2 , Susana Guix  2
Affiliations
Review

Human astroviruses

Albert Bosch et al. Clin Microbiol Rev. 2014 Oct.

Abstract

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 genera Mamastrovirus and Avastrovirus. Through next-generation sequencing, many new astroviruses infecting different species, including humans, have been described, and the Astroviridae family 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 8 and MAstV 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.

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Figures

FIG 1
FIG 1
Human astrovirus particles observed by transmission immunoelectron microscopy in feces negatively stained with phosphotungstic acid. Bar, 50 nm.
FIG 2
FIG 2
Genome organization and polyprotein products of human astrovirus. (A) Genomic and subgenomic RNA organization, with open reading frames (ORFs) ORF1a, ORF1b, ORF2, and putative ORFX represented as boxes. Nucleotide sequences represent highly conserved sequences located in the ribosomal frameshift (RFS) signal and upstream of the initiation site of subgenomic RNA transcription. Putative RNA secondary structures conserved in the RFS and in the 3′ end of the genome are depicted. (B) Characteristic motifs of the HAstV polyprotein products. HEL, putative helicase domain; TM, transmembrane domain; CC, coiled-coil domain; PRO, protease domain; VPg, coding region for a VPg protein; HVR, hypervariable region; NLS, putative nuclear localization signal; DD, putative death domain; RdRp, RNA dependent-RNA polymerase motif. The ORF2-encoded structural polyprotein (VP90) consists of conserved regions (shell and P1 domains), a variable region containing the P2 domain (capsid spikes), and an acidic C-terminal region which is cleaved by cellular caspases to result in the VP70 precursor. Particles containing VP70 are further cleaved by trypsin to yield the VP34, VP27/29, and VP25/26 proteins.
FIG 3
FIG 3
Replication of human astroviruses. After binding to one or more cellular receptors, virus uptake occurs via clathrin-dependent endocytosis. A drop in the pH leads to viral uncoating. Two main nonstructural polyproteins, nsP1a and nsP1a1b, are translated from the VPg-linked genomic RNA and further cleaved by viral and cellular proteases, resulting in mature nonstructural proteins (nsPs), which are required for genome replication. Replication complexes assemble in close association with intracellular membranes. The nsP1a/4 protein or one of its precursors, which would include the VPg domain, may interact with the RdRp protein and contribute to the regulation of the synthesis of negative- and positive-sense RNA strands as well as of subgenomic RNA. The phosphorylation status of the nsP1a/4 protein may contribute to this regulation step. Subgenomic RNAs are produced in large quantities and are used for the expression of capsid proteins. The structural VP90 polyprotein initially assembles into immature virions in association with intracellular membranes. Several cellular caspases further cleave these VP90 polyproteins once they have dissociated from membranes, resulting in VP70 immature viral capsids. Release of VP70 particles into the medium seems to occur without cell lysis, and virions mature extracellularly by the action of trypsin.
FIG 4
FIG 4
Putative processing of the astrovirus nonstructural proteins expressed from ORF1a and ORF1b. HEL, putative helicase domain; CC, coiled-coil domain; TM, transmembrane domain; PRO, protease domain; VPg, viral protein genome-linked coding region; HVR, hypervariable region; RdRp, RNA-dependent RNA polymerase motif; P, posttranslational phosphorylation. Triangles depict proteolytic cleavage sites described in the literature (75, 77, 78, 80).
FIG 5
FIG 5
HAstV particles are associated with membranes in infected cells. Ultrastructural analysis of CaCo-2 cells infected with HAstV-4 at 48 h postinfection shows aggregates of virions accumulated in the cytoplasm in close association with double-membrane vesicles (V). Nuclei (N) of infected cells show masses of condensed chromatin dispersed at the periphery (c).
FIG 6
FIG 6
Phylogenetic relationships within the family Astroviridae. The predicted amino acid sequences of the entire capsid polyprotein were aligned using Clustal Omega (309). The phylogenetic tree was generated using the neighbor-joining algorithm (310) implemented in the MEGA6 program (311). The percentages of replicate trees in which the associated taxa clustered together in the bootstrap test (1,000 replicates) which are higher than 70 are shown next to the branches. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances (p-dist) used to infer the phylogenetic tree. All positions containing alignment gaps and missing data were removed only in pairwise sequence comparisons (pairwise deletion option). Genotype species officially recognized by the ICTV are indicated, with hosts of origin shown in parentheses. Human viruses are colored in red, porcine viruses are colored in dark blue, mink viruses are colored in dark gray, bovine viruses are colored in brown, ovine viruses are colored in light blue, bat viruses are colored in black, murine viruses are colored in purple, turkey viruses are colored in orange, and chicken viruses are colored in green. Arrows indicate strains which have been isolated from neurologic tissues. HAstV, human astrovirus; FAstV, feline astrovirus; PAstV, porcine astrovirus; CaAstV, canine astrovirus; RabAstV, rabbit astrovirus; OAstV, ovine astrovirus; BoAstV, bovine astrovirus; MuAstV, murine astrovirus; WBAstV, wild boar astrovirus; CcAstV, deer astrovirus; TAstV, turkey astrovirus; CAstV, chicken astrovirus; ANV, avian nephritis virus; WPIAstV, wild pigeon astrovirus.
FIG 7
FIG 7
Flowchart of potential routes of environmental transmission of human astroviruses (see the text for details).
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