Conservation of fiber structure and CD46 usage by subgroup B2 adenoviruses

Pache, Lars; Venkataraman, Sangita; Nemerow, Glen R.; Reddy, Vijay

doi:10.1016/j.virol.2008.02.013

Cited by 24 publications

(33 citation statements)

References 25 publications

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“…To determine if the observed structural variations overlap cellular receptor binding sites, we mapped the known HAdV-cellular receptor interactions for CAR, CD46, and GD1a glycan on the homology model (16,20,32,44,(48)(49)(50)(51)(52)(53)(54). The two structural variations viewed in a surface filled model (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…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)(7)(8)(9)(10)(11)(12). Each of these has been associated with epidemic keratoconjunctivitis (EKC), a highly contagious ocular surface infection (13).…”

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confidence: 99%

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

Ismail

Lee

Dyer

et al. 2016

J Virol

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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...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Ismail

Lee

Dyer

et al. 2016

J Virol

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“…To date, most studies have focused on the mechanism of receptor binding by two species B2 Ads, Ad11 and Ad35. Recent investigations found that both viruses engage CD46 in a similar fashion and with similar efficiencies (23,24,37). Based on the cocrystal structure of the Ad11 fiber knob in complex with CD46, a large continuous binding region in the virus fiber was shown to encompass the DG, HI, and IJ loops of the fiber knob.…”

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confidence: 99%

Structural Variations in Species B Adenovirus Fibers Impact CD46 Association

Pache

Venkataraman

Reddy

et al. 2008

J Virol

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“…Recent studies have revealed the structure of species B Ad fiber knobs, the mode of interaction with CD46 and several amino acids crucial for CD46 binding in the fiber knob, [28][29][30][31] and that the FG, HI and IJ loops are involved in the association with CD46. [31][32][33] In particular, Phe242 in the FG loop, Arg279 and Ser282 in the HI loop, and Glu302 in the IJ loop are crucial for attachment to CD46 (note that the numbers of amino-acid residues are those of the Ad35 fiber knob). 31 A unique XbaI restriction site was introduced into the proximity of regions encoding these amino-acid residues, between Gln243 and Thr244 in the FG loop, Met280 and Ile281 in the HI loop, or Glu302 and Ser303 in the IJ loop, in the vector plasmid for AdF35 vectors to allow easy insertion of the oligonucleotides corresponding to foreign peptides by means of in vitro ligation.…”

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confidence: 99%

“…An increase in the luciferase production was not observed for the AdF35 vectors with foreign peptides inserted in the IJ loop. The IJ loop of the Ad35 fiber knob is far from the short consensus repeat (SCR)2 in human CD46, compared with Ad serotypes 7 and 11 (Ad11), 28,[30][31][32] suggesting that an RGD peptide inserted into the IJ loop might not be able to make contact with CD46. Unexpectedly, AdF35-FLAG(HI)-L2 also showed increased transduction efficiencies in both cell types.…”

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confidence: 99%

Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

et al. 2009

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Fiber-substituted adenovirus (Ad) vectors containing fibers of Ad serotype 35 (AdF35) efficiently transduce a variety of human cells because their receptor, human CD46, is ubiquitously expressed on almost all nucleated cells. However, the ubiquitous expression of CD46 might lead to unexpected transduction in untargeted organs. In this study, we developed fiber-modified AdF35 vectors with an integrinbinding Arg-Gly-Asn (RGD) peptide incorporated into the FG, HI or IJ loop, which have been identified as important regions for binding to CD46. Incorporation of foreign peptides into these loops does not inhibit trimerization of the fibers. In CD46-negative cells, fiber-mutant AdF35 vectors containing an RGD peptide in the FG or HI loop showed 6-to 30-fold higher transduction efficiencies in an RGD-peptide-dependent manner than the unmodified AdF35 vectors. In contrast, in CD46-positive cells, insertion of foreign peptides markedly reduced the transduction efficiencies of the AdF35 vectors, indicating that insertion of foreign peptides significantly inhibits binding to CD46. In particular, CD46-mediated transduction was completely diminished by insertion of foreign peptides into the HI loop. Our findings indicate that HI loop is the most suitable domain to mediate a foreign peptide-dependent and CD46-independent transduction by incorporation of foreign peptides into the Ad35 fiber knob.

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Conservation of fiber structure and CD46 usage by subgroup B2 adenoviruses

Cited by 24 publications

References 25 publications

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

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

Structural Variations in Species B Adenovirus Fibers Impact CD46 Association

Development of fiber-substituted adenovirus vectors containing foreign peptides in the adenovirus serotype 35 fiber knob

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