Characterization of species C human adenovirus serotype 6 (Ad6)

Weaver, Eric A.; Hillestad, Mathew L.; Khare, Reeti; Palmer, D. Jason; Ng, Philip; Barry, Michael A.

doi:10.1016/j.virol.2010.10.041

Cited by 31 publications

(59 citation statements)

References 28 publications

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“…These data implicate the HVRs of the Ad5 hexon in two pharmacologic bottlenecks after i.v. injection of the virus: (i) binding or evasion of Kupffer cells and (ii) binding of FX and retargeting to hepatocytes.We recently compared the biology of Ad5 with another species C adenovirus, Ad6 (18,34). In these studies, we found that native Ad6 mediates higher liver transduction than Ad5 after i.v.…”

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confidence: 99%

Identification of Adenovirus Serotype 5 Hexon Regions That Interact with Scavenger Receptors

Khare

Reddy

Nemerow

et al. 2012

J Virol

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Most of an intravenous dose of species C adenovirus serotype 5 (Ad5) is destroyed by liver Kupffer cells. In contrast, another species C virus, Ad6, evades these cells to mediate more efficient liver gene delivery. Given that this difference in Kupffer cell interaction is mediated by the hypervariable (HVR) loops of the virus hexon protein, we genetically modified each of the seven HVRs of Ad5 with a cysteine residue to enable conditional blocking of these sites with polyethylene glycol (PEG). We show that these modifications do not affect in vitro virus transduction. In contrast, after intravenous injection, targeted PEGylation at HVRs 1, 2, 5, and 7 increased viral liver transduction up to 20-fold. Elimination or saturation of liver Kupffer cells did not significantly affect this increase in the liver transduction. In vitro, PEGylation blocked uptake of viruses via the Kupffer cell scavenger receptor SRA-II. These data suggest that HVRs 1, 2, 5, and 7 of Ad5 may be involved in Kupffer cell recognition and subsequent destruction. These data also demonstrate that this conditional genetic-chemical mutation strategy is a useful tool for investigating the interactions of viruses with host tissues.A denovirus serotype 5 (Ad5) has proven to be one of the most potent in vivo gene delivery vectors for liver-directed gene therapy. As much as 95 to 98% of an intravenously (i.v.) injected dose of Ad5 is trafficked to the liver (12). The adenovirus capsid is comprised of three major proteins: hexon, penton base, and fiber (reviewed in reference 7). Based on numerous in vitro studies, adenovirus fiber and penton base have been shown to be cellular attachment proteins. The fiber of Ad5 binds coxsackie and adenovirus receptor (CAR) (3), which triggers binding of penton base to ␣v integrins via an RGD motif (35,36) and results in viral cell internalization. Although necessary for providing specificity of the virus in vitro, modifications to the fiber have little effect on vector tropism in vivo (25). Instead, increasing evidence suggests that hexon plays a large role in the natural liver tropism of Ad5.Hexon is the most abundant viral capsid protein with 720 monomers per virion. Hexon organizes into trimers so that three hexon monomers and their loops wrap tightly around each other to create a tower-like structure with a central depression (20,28). Each hexon monomer has seven flexible, serotype-specific loops, named hypervariable regions (HVRs) (23), that are predicted to be located on the surface of the hexon trimer and the virion (29). This location allows the HVRs of hexon to interact with neutralizing antibodies, receptors, proteins, and cells. Considering there are 5,040 (720 ϫ 7 ϭ 5,040) HVRs per virion, these represent a complex, exposed surface for many interactions.After i.v. injection, Ad5 exhibits the greatest transduction within liver hepatocytes (12). Despite this robust in vivo gene delivery, ϳ90% of the injected dose is sequestered and destroyed by resident liver macrophages called Kupffer cells (1). These anti...

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Identification of Adenovirus Serotype 5 Hexon Regions That Interact with Scavenger Receptors

Khare

Reddy

Nemerow

et al. 2012

J Virol

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“…This has led to the evaluation of alternate adenoviral serotypes to avoid immune neutralization (14,49). In the course of our work on oncolytic virotherapy, we identified species C Ad6 and species D Ad26 as two promising lower-seroprevalence viruses (2,12,16,18,(50)(51)(52)). Ad6 appears promising as an oncolytic agent against prostate cancer, whereas Ad26 holds promise against B cell malignancies.…”

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confidence: 99%

“…Human mastadenoviruses (HAdVs) fall into genetically grouped species A (HAdV-A) through species G (HAdV-G), with the level of sequence diversity across the virome being as high as 40% (2). Despite this drastic genetic diversity, the biology of most Ads is often extrapolated from the study of just two respiratory serotypes of HAdV-C, Ad2 and Ad5.…”

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“…While these analyses provide useful insights into the biology of each virus, it is unclear in these separate studies how these two viruses or any two adenoviruses may execute their transcriptional programs in similar or different ways. Human Ad6 falls into species C with Ad2 and Ad5 and shares 98 and 94% identities at the DNA level, respectively (2). Ad6 was originally isolated from the tonsils of a child and is generally thought to be a respiratory virus like other species C viruses (9).…”

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“…Both Ad6 and Ad26 are thought to infect different initial sites, but both viruses are shed from the digestive track for months after infection (1). Ad6 and Ad26 differ at the DNA genome level by 34% and represent two ends of the viral phylogenetic tree (2). Like other HAdV-C serotypes, Ad6 uses the coxsackievirus and adenovirus receptor (CAR) and ␣v integrins as well as binds vitamin K-dependent clotting factors that modulate its pharmacology (reviewed in reference 10).…”

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Comparison of the Life Cycles of Genetically Distant Species C and Species D Human Adenoviruses Ad6 and Ad26 in Human Cells

Turner

Middha

Hofherr

et al. 2015

J Virol

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Our understanding of adenovirus (Ad) biology is largely extrapolated from human species C Ad5. Most humans are immune to Ad5, so lower-seroprevalence viruses like human Ad6 and Ad26 are being tested as therapeutic vectors. Ad6 and Ad26 differ at the DNA level by 34%. To better understand how this might impact their biology, we examined the life cycle of the two viruses in human lung cells in vitro. Both viruses infected A549 cells with similar efficiencies, executed DNA replication with identical kinetics within 12 h, and began killing cells within 72 h. While Ad6-infected cells remained adherent until death, Ad26-infected cells detached within 12 h of infection but remained viable. Next-generation sequencing (NGS) of mRNA from infected cells demonstrated that viral transcripts constituted 1% of cellular mRNAs within 6 h and 8 to 16% within 12 h. Quantitative PCR and NGS revealed the activation of key early genes at 6 h and transition to late gene activation by 12 h by both viruses. There were marked differences in the balance of E1A and E1B activation by the two viruses and in the expression of E3 immune evasion mRNAs. Ad6 was markedly more effective at suppressing major histocompatibility complex class I (MHC I) display on the cell surface and in evading TRAIL-mediated apoptosis than was Ad26. These data demonstrate shared as well as divergent life cycles in these genetically distant human adenoviruses. An understanding of these differences expands the knowledge of alternative Ad species and may inform the selection of related Ads for therapeutic development. IMPORTANCEA burgeoning number of adenoviruses (Ads) are being harnessed as therapeutics, yet the biology of these viruses is generally extrapolated from Ad2 and Ad5. Here, we are the first to compare the transcriptional programs of two genetically distant Ads by mRNA next-generation sequencing (NGS). Species C Ad6 and Ad26 are being pursued as lower-seroprevalence Ad vectors but differ at the DNA level by 34%. Head-to-head comparison in human lung cells by NGS revealed that the two viruses generally conform to our general understanding of the Ad transcriptional program. However, fine mapping revealed subtle and strong differences in how these two viruses execute these programs, including differences in the balance of E1A and E1B mRNAs and in E3 immune evasion genes. This suggests that not all adenoviruses behave like Ad2 and Ad5 and that they may have unique strategies to infect cells and evade the immune system. T here are currently nearly 60 genotypes of adenoviruses (Ads) that infect humans, causing an array of ocular, respiratory, digestive, and systemic infections (reviewed in reference 1). Human mastadenoviruses (HAdVs) fall into genetically grouped species A (HAdV-A) through species G (HAdV-G), with the level of sequence diversity across the virome being as high as 40% (2). Despite this drastic genetic diversity, the biology of most Ads is often extrapolated from the study of just two respiratory serotypes of HAdV-C, Ad2 and Ad5.Transcripti...

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Retargeting adenoviruses for therapeutic applications and vaccines

Barry

Rubin

2020

FEBS Letters

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Adenoviruses (Ads) are robust vectors for therapeutic applications and vaccines, but their use can be limited by differences in their in vitro and in vivo pharmacologies. This review emphasizes that there is not just one Ad, but a whole virome of diverse viruses that can be used as therapeutics. It discusses that true vector targeting involves not only retargeting viruses, but importantly also detargeting the viruses from off-target cells.

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Characterization of species C human adenovirus serotype 6 (Ad6)

Cited by 31 publications

References 28 publications

Identification of Adenovirus Serotype 5 Hexon Regions That Interact with Scavenger Receptors

Identification of Adenovirus Serotype 5 Hexon Regions That Interact with Scavenger Receptors

Comparison of the Life Cycles of Genetically Distant Species C and Species D Human Adenoviruses Ad6 and Ad26 in Human Cells

Retargeting adenoviruses for therapeutic applications and vaccines

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