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Aichivirus A
Aichivirus A formerly Aichi virus (AiV)[1] belongs to the genus Kobuvirus in the family Picornaviridae.[2] Six species are part of the genus Kobuvirus, Aichivirus A-F.[3] Within Aichivirus A, there are six different types including human Aichi virus, canine kobuvirus, murine kobuvirus, Kathmandu sewage kobuvirus, roller kobuvirus, and feline kobuvirus.[3] Three different genotypes are found in human Aichi virus, represented as genotype A, B, and C.[3] AiV is a non-enveloped positive sense ssRNA virus with icosahedral morphology.[3] Aichivirus A was originally identified after a 1989 outbreak of acute gastroenteritis in the Aichi Prefecture that was linked to raw oyster consumption per genetic analysis.[1][4][5] Human Aichi Virus can cause gastroenteritis with symptoms arising such as vomiting, diarrhea, abdominal pain, nausea, and feve.[3][6] Aichivirus A can be found in a variety of environmental areas including sewage, groundwater, river water, and shellfish.[2] Aichivirus A is present in many world regions, and in sometimes greater abundance than other well-known enteric viruses.[2] Aichiviruses have been seen in Asia, Europe, South America, and Africa.[2] It has since been isolated in populations of Finnish children,[7] Pakistani children, and Japanese travelers.[8] The widespread nature of aichivirus A can be seen in the high percentage of AiV antibodies in adult human populations found in several countries.[3] Transmission occurs through the fecal-oral route.[2] After the virus is replicated in the gastrointestinal tract, the pathogen can be found in fecal samples of infected individuals.[2] Water and shellfish contaminated with human sewage can propagate aichivirus A.[2] Discovery Aichivirus A was first characterized after an outbreak of gastroenteritis in the Aichi Prefecture of Japan, this region is where the name of the virus was derived from.[5] Fecal samples from infected individuals were taken and transported to a lab where they described the novel virus.[5] These viral particles were 30 nm in diameter, a spherical shape, and cytopathic for BSC-1 cells (kidney cells of African green monkey).[3][5] The infection was attributed to contaminated raw oyster found in vinegar.[5] Aichivirus A has been seen and described across many Asian countries, however the first appearance of aichivirus outside of this region was isolated in Europe and South America in 2006.[9] Through genetic analysis of isolates from Brazil and Germany, the nucleotide sequences were found to be similar to known Aichivirus nucleotide sequences.[9] Notably, the German strain appeared to be of genotype A and the Brazil strain appeared to be of genotype B.[9] Screening in Germany for antibodies to Aichivirus displayed a seroprevalence of 76%, which is comparable to seroprevalence in Japan.[9] Therefore, European infection with Aichivirus is as common as it is in Asia.[9] Human infection_RNA_synthesis.svg) PropagationAichivirus A enters host cells through receptor-mediated endocytosis, a cellular uptake mechanism.[3] After viral attachment and entry, the virion particle is uncoated releasing the genome into the cytoplasm.[3] Similar to other viruses within the Picornaviridae family, viral replication and translation occurs in the cytoplasm.[10] The positive sense ssRNA is directly translated into protein by the host cell ribosomes, while some of the ssRNA is used as a template to replicate the viral genome. Capsid proteins, L protein, nonstructural proteins, and stable intermediates are produced after the polyprotein is processed. Protein production is directly related to synthesis of plus-strand RNA replication complex.[10][3] The plus-strand RNA genome is packaged into the assembled viral particle, along with VpG (Viral genomic protein).[3] A completed viral particle has 60 capsid proteins copies made up of 12 pentamers.[3] The pentamer is made up by the 5S subunit composed of VP0, VP1, and VP3 protein aggregates.[3] After the viral particle is assembled, it is released from host cells by cell lysis, making Aichivirus A a lytic virus.[3][11] CharacteristicsMost aichivirus A infection in humans are mild, asymptomatic infections lasting between 48–72 hours.[3] However, it can develop into the common symptoms of gastroenteritis: fever, nausea, vomiting, abdominal pain.[12][3] Viral replication in the gastrointestinal tract damages the enterocyte layer in the intestinal villi interfering with water reabsorption[12] This can lead to the symptoms appearing with infection. Aichivirus A can become an opportunistic pathogen in those with HIV and is seen in high levels in the feces of those with HIV.[13][14] Aichivirus A is also suspected as an opportunistic pathogan in those with X-linked agammaglobulinemia.[14] Aichivirus is an emerging pathogen in those with B-cell deficiencies, however there is no explanation why[14] In patients with primary immune deficiencies, chronic aichivirus infection can cause immunodysregulation.[15] Human aichivirus was deemed to effect multiple organs leading to the clinical symptom presentation.[15] The aichivirus genome was detected in symptomatic patients and in infected organs, while it was not seen in asymptomatic individuals.[15] Notably, in Japan there is a correlation with aichivirus A infection and lower respiratory tract disease.[16] Genome The RNA genome of AiV A is composed of 8280 nucleotides. Along the 5' end of the RNA, there is an untranslated region consisting of 744 nucleotides, a VpG protein, and an internal ribosomal entry site (IRES). Following the 5' untranslated region, the open reading frame is approximately 7.3kB consisting of 2432 amino acids. The L protein, leader peptide, is the first protein translated within the polypeptide, followed by the structural proteins, and then nonstructural proteins. Cleavage into the different proteins occurs by viral proteases.[17] The capsid proteins are made up of three segments in the RNA: VP0, VP3, and VP1.[3][17] These capsid proteins together are known as the P1 region on the genome.[3] The encoded capsid proteins form a protomer that form into 12 pentamers during self-assembly.[17][18] X-ray crystallography of human aichi virus virion structure determined that the VP3 knob structure and VP0 surface loop are smaller compared to other viruses in picornaviruses.[17] P2 and P3 are the regions of the RNA genome that are the non-structural proteins involved in replication control.[17][19] For example, the protein 3D within the P3 region encodes for the viral RNA-dependent RNA polymerase used in replication.[20] The 3B protein also in the P3 region encodes for the VpG protein, which is important promoting replication. Following the P2 and P3 region, there is a 3' untranslated region of about 237 nucleotides and a poly-A tail.[3] Genotypic differencesDifferences at the 3CD nonstructural protein junction in the viral genome results in distinct genotypic differences.[21][3] When comparing the junction between the C-terminus of the 3C region and the N-terminus of the 3D region, three distinct genotypic types are seen.[3] In studies, there appeared to be a geographical distribution to the genotypes. In some countries genotype B is prevalent, while in others genotype A dominates. In Finland and Spain genotype A was more prevalent.[7][22] However, in China, Bangladesh, and Pakistan genotype B is more widely seen in gastroenteritis outbreaks.[23][24] However, genotype C is not widely seen to cause human infection and has only been described in one study a fecal sample from a child case of gastroenteritis after a trip to Mali.[3][21] The VP1 region is used to classify the picornaviruses and can also be used to differentiate between aichivirus A genotypes.[3] Some studies have seen more variation in the VP1 region and suggest that this region may be a better region to differentiate between genotypes.[9] Environmental occurrenceAichivirus A can be found in a variety of environmental sources potentially leading to infection through food and water consumption. Aichivirus A causes infection through the fecal-oral route, where contaminated food and water sources are ingested.[3] Some studies suggest using Aichivirus A as a method to detect viral contamination in environmental samples.[2]  ShellfishEnteric viruses can propagate through bivalve mollusks which filter surrounding water for food and retain enteric viruses.[3] Many safety protocols only take into account bacteria and not viruses, which makes shellfish a vector for viral transmission.[25] Aichivirus A was first detected in an outbreak due to contaminated oysters, and contaminated seafood has been associated with aichivrius A outbreaks worldwide.[3] In a year-long study in Japan on viral detection in clams, 33% of the grocery store samples contained aichivirus A.[26] SewageAichivirus A has been reported at high rates in wastewater but was first seen in 2010.[27] Wastewater treatment cannot get rid of all the viral particles before being discharged into the environment.[3] Due to the stability of aichivirus in sewage before and after treatment, aichivirus A is likely a human fecal pollutant indicator.[3] Aichivirus A has been detected in wastewater in America, Europe, Africa, and Asia.[3] In one study, samples of treated sewage contained a 91.7% prevalence of aichivirus A.[28] River and ground waterRiver water and ground water can be a reservoir for aichivirus A, due to viruses not being removed during the natural filtration cycle.[3] Aichivirus A was first studied in river water in Venezuela in 2010 with detection in 45% of samples.[27] Aichivirus A has since been detected in water sources worldwide, including in tap water and ground water in America.[3] ResearchUnder an electron microscope, Aichivirus A appears as a small, round virus making it hard to distinguish it from other viruses with a similar morphology.[16] Under electron microscopy, a canyon-like valley is seen on the surface of the capsid, likely where receptor binding occurs for entry.[3] The viral particle is stable in acidic conditions until a pH of 2 and remains stable under known experimental methods to disrupt the viral particle.[29] These methods include heat, hydrostatic pressure, and detergent conditions.[29][3] In human cell lines like HeLa, a cytopathic effect is not seen, however a cytopathic effect is seen in BSC-1 cell lines and Vero Cells.[3] An enzyme-linked immunoabsorbant assay (ELISA) has been developed to detect aichivirus A antigens.[16] Reverse transcription-RNA polymerase chain reaction is also widely used in aichivirus research for identification and genotype differentiation.[30] A loop-mediated isothermal amplification (LAMP) assay has been created for aichivirus A to be used in water samples.[31] The LAMP assay allows for a rapid and specific detection of aichivirus A.[31] Reverse transcription-quantitative PCR (RT-qPCR) is also widely used for detection and to determine viral numbers.[3] References
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