Overreliance on the Hexon Gene, Leading to Misclassification of Human Adenoviruses

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e Genes within the E3 transcription unit of human adenoviruses modulate host immune responses to infection. A comprehensive genomics and bioinformatics analysis of the E3 transcription unit for 38 viruses within human adenovirus species D (HAdV-D) revealed distinct and surprising patterns of homologous recombination. Homologous recombination was identified in open reading frames for E3 CR1␣, CR1␤, and CR1␥, similar to that previously observed with genes encoding the three major structural capsid proteins, the penton base, hexon, and fiber.

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confidence: 61%

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confidence: 99%

Homologous Recombination in E3 Genes of Human Adenovirus Species D

Singh

Robinson

Dehghan

et al. 2013

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“…Lys345 was suggested to play a crucial role in HAdV-D37 binding to sialic acid (59). Similarly, lysine residues are involved in HAdV-CAR interactions (4,24).…”

Section: Discussionmentioning

confidence: 99%

Selection Pressure in the Human Adenovirus Fiber Knob Drives Cell Specificity in Epidemic Keratoconjunctivitis

Ismail

Lee

Dyer

et al. 2016

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Human adenoviruses (HAdVs) contain seven species (HAdV-A to -G), each associated with specific disease conditions. Among these, HAdV-D includes those viruses associated with epidemic keratoconjunctivitis (EKC), a severe ocular surface infection. The reasons for corneal tropism for some but not all HAdV-Ds are not known. The fiber protein is a major capsid protein; its C-terminal "knob" mediates binding with host cell receptors to facilitate subsequent viral entry. In a comprehensive phylogenetic analysis of HAdV-D capsid genes, fiber knob gene sequences of HAdV-D types associated with EKC formed a unique clade. By proteotyping analysis, EKC virus-associated fiber knobs were uniquely shared. Comparative structural modeling showed no distinct variations in fiber knobs of EKC types but did show variation among HAdV-Ds in a region overlapping with the known CD46 binding site in HAdV-B. We also found signature amino acid positions that distinguish EKC from non-EKC types, and by in vitro studies we showed that corneal epithelial cell tropism can be predicted by the presence of a lysine or alanine at residue 240. This same amino acid residue in EKC viruses shows evidence for positive selection, suggesting that evolutionary pressure enhances fitness in corneal infection, and may be a molecular determinant in EKC pathogenesis. IMPORTANCEViruses adapt various survival strategies to gain entry into target host cells. Human adenovirus (HAdV) types are associated with distinct disease conditions, yet evidence for connections between genotype and cellular tropism is generally lacking. Here, we provide a structural and evolutionary basis for the association between specific genotypes within HAdV species D and epidemic keratoconjunctivitis, a severe ocular surface infection. We find that HAdV-D fiber genes of major EKC pathogens, specifically the fiber knob gene region, share a distinct phylogenetic clade. Deeper analysis of the fiber gene revealed that evolutionary pressure at crucial amino acid sites has a significant impact on its structural conformation, which is likely important in host cell binding and entry. Specific amino acids in hot spot residues provide a link to ocular cell tropism and possibly to corneal pathogenesis. Human adenoviruses (HAdVs) are major causes of respiratory disease, gastroenteritis, and keratoconjunctivitis (1-4). HAdV infections are also a major concern in immunocompromised hosts, with fatality rates as high as 55% (5). There are 72 HAdVs currently genotyped in GenBank, which are classified into seven species (HAdV-A to -G) as determined by whole-genome analysis. The majority (n ϭ 47) belong to HAdV-D, including types 8, 37, 53, 54, 56, and 64 (6-12). Each of these has been associated with epidemic keratoconjunctivitis (EKC), a highly contagious ocular surface infection (13). HAdV-D evolves by homologous recombination within genes encoding the major HAdV capsid proteins (14). For example, type 64 (previously typed as 19a) is a recombinant with types 19, 22, and 37 in the hexon, penton ba...

“…To date, 65 HAdV types have been recognized and classified within seven species (5,6,8,(10)(11)(12). Among these, HAdV-B14 has been rarely reported since its identification as an acute respiratory pathogen in The Netherlands in 1955, with a second occurrence in England (1957).…”

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confidence: 99%

Genome Sequence of the First Human Adenovirus Type 14 Isolated in China

Zhang

Seto

Zhao

et al. 2012

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Emergent pathogens may be examined rapidly at high resolution on a molecular level using genomics, allowing an understanding of their evolution. China is a unique environment for studying pathogens, having a large, dense, and generally closed population. Human adenovirus type 14 (HAdV-14) was originally identified as an acute respiratory disease (ARD) pathogen in The Netherlands (1955), with a second isolation in England (1957). Since then, few reports of this virus appeared until an ARD pathogen with a similar genome caused multiple outbreaks in the United States (2006 to 2009). This report presents the first genome of HAdV-B14 isolated in China (2010). As China experienced two recent outbreaks of an emergent ARD pathogen, HAdV-B55, containing much of the HAdV-B14 genome, the availability of this HAdV-B14 sequence will facilitate studies of the epidemiology of these pathogens, as well as provide a foundation for studying adenovirus evolution and the genesis of emergent pathogens. These observations may be invaluable in predicting possible recombination between wild-type viruses and adenoviral gene delivery vectors, including adenovirus vaccines.