Crystal Structure of Enteric Adenovirus Serotype 41 Short Fiber Head

ABSTRACT Human enteric adenoviruses of species F contain two fibers in the same virion, a long fiber which binds to coxsackievirus and adenovirus receptor (CAR) and a short fiber of unknown function. We have determined the high-resolution crystal structure of the short fiber head of human adenovirus serotype 41 (Ad41). The short fiber head has the characteristic fold of other known fiber heads but has three unusual features. First, it has much shorter loops between the beta-strands. Second, one of the usually well-ordered beta-strands on the distal face of the fiber head is highly disordered and this same region is sensitive to digestion with pepsin, an enzyme occurring naturally in the intestinal tract, the physiological environment of Ad41. Third, the AB loop has a deletion giving it a distinct conformation incompatible with CAR binding.

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Reduction of Natural Adenovirus Tropism to the Liver by both Ablation of Fiber-Coxsackievirus and Adenovirus Receptor Interaction and Use of Replaceable Short Fiber

Journal of Virology ◽

10.1128/jvi.77.4.2512-2521.2003 ◽

2003 ◽

Vol 77 (4) ◽

pp. 2512-2521 ◽

Cited By ~ 84

Author(s):

Takafumi Nakamura ◽

Kenzo Sato ◽

Hirofumi Hamada

Keyword(s):

Gene Transfer ◽

Adenovirus Vector ◽

Short Fiber ◽

Transduction Efficiency ◽

Target Cells ◽

Shaft Length ◽

Adenovirus Serotype ◽

Coxsackievirus And Adenovirus Receptor ◽

Adenovirus Receptor

ABSTRACT The initial recognition and binding of adenovirus vector to the host cell surface is mediated by interaction between the adenovirus fiber knob protein and its receptor, the coxsackievirus and adenovirus receptor (CAR). This natural tropism of adenovirus vector needs to be ablated in order to achieve targeted gene transfer. To this end, we noted that adenovirus serotype 40 (Ad40) contains two distinct long and short fibers; the short fiber is unable to recognize CAR, while the long fiber binds CAR. We generated adenovirus serotype 5-based mutants with chimeric Ad40-derived fibers, which were composed of either long or short shafts together with CAR binding or nonbinding knobs. The capacity of these adenovirus mutants for in vitro and in vivo gene transfer to liver cells was examined. In the case of primary human hepatocytes displaying a high expression level of CAR and αv integrin, both CAR binding ability and fiber shaft length played important roles in efficient transduction. Most significantly, the high transduction efficiency observed in the liver and spleen following intravenous administration of adenovirus vector was dramatically reduced by both ablation of fiber-CAR interaction and the use of replaceable short fiber. In other tissues displaying a low level of transduction, no significant differences in transduction efficiency were observed among adenovirus vector mutants. Furthermore, incorporation of a 7-lysine-residue motif at the C-terminal end of CAR-nonbinding short fiber efficiently achieved transduction of target cells via the heparan-containing receptor. Our results demonstrated that the natural tropism of adenovirus in vivo is influenced not only by fiber-CAR interaction but also by fiber shaft length. Furthermore, our strategy may be useful for retargeting adenovirus to particular tumors and tissue types with specific receptors.

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Heparan Sulfate Is a Cellular Receptor for Enteric Human Adenoviruses

Viruses ◽

10.3390/v13020298 ◽

2021 ◽

Vol 13 (2) ◽

pp. 298

Author(s):

Anandi Rajan ◽

Elin Palm ◽

Fredrik Trulsson ◽

Sarah Mundigl ◽

Miriam Becker ◽

...

Keyword(s):

Heparan Sulfate ◽

Vaccine Development ◽

Antiviral Drug ◽

Human Adenovirus ◽

Short Fiber ◽

Host Cells ◽

Acidic Ph ◽

Enteric Adenovirus ◽

Fiber Proteins ◽

Adenovirus Receptor

Human adenovirus (HAdV)-F40 and -F41 are leading causes of diarrhea and diarrhea-associated mortality in children under the age of five, but the mechanisms by which they infect host cells are poorly understood. HAdVs initiate infection through interactions between the knob domain of the fiber capsid protein and host cell receptors. Unlike most other HAdVs, HAdV-F40 and -F41 possess two different fiber proteins—a long fiber and a short fiber. Whereas the long fiber binds to the Coxsackievirus and adenovirus receptor (CAR), no binding partners have been identified for the short fiber. In this study, we identified heparan sulfate (HS) as an interaction partner for the short fiber of enteric HAdVs. We demonstrate that exposure to acidic pH, which mimics the environment of the stomach, inactivates the interaction of enteric adenovirus with CAR. However, the short fiber:HS interaction is resistant to and even enhanced by acidic pH, which allows attachment to host cells. Our results suggest a switch in receptor usage of enteric HAdVs after exposure to acidic pH and add to the understanding of the function of the short fibers. These results may also be useful for antiviral drug development and the utilization of enteric HAdVs for clinical applications such as vaccine development.

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Chimpanzee adenovirus CV-68 adapted as a gene delivery vector interacts with the coxsackievirus and adenovirus receptor

Journal of General Virology ◽

10.1099/0022-1317-83-1-151 ◽

2002 ◽

Vol 83 (1) ◽

pp. 151-155 ◽

Cited By ~ 43

Author(s):

Christopher J. Cohen ◽

Zhi Quan Xiang ◽

Guang-Ping Gao ◽

Hildegund C. J. Ertl ◽

James M. Wilson ◽

...

Keyword(s):

Gene Delivery ◽

Cho Cells ◽

Human Adenovirus ◽

Adenovirus Type ◽

Soluble Form ◽

Delivery Vector ◽

Coxsackievirus And Adenovirus Receptor ◽

Adenovirus Receptor ◽

Adenovirus Type 5 ◽

Dependent Mechanism

A replication-defective form of chimpanzee adenovirus type 68 (C68) has been developed to circumvent problems posed by widespread preexisting immunity to common human adenovirus vectors. To investigate the determinants of C68 tropism, its interaction with the coxsackievirus and adenovirus receptor (CAR) was studied. Although CHO cells were resistant to transduction by C68 as well as by adenovirus type 5 (Ad5), CHO cells expressing either human or murine CAR were transduced readily. C68 transduction, like Ad5 transduction, was blocked when cells were exposed to anti-CAR antibody or when virus was exposed to a soluble form of the CAR extracellular domain. These results indicate that gene delivery by C68 occurs by a CAR-dependent mechanism.

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Replication-Defective Vector Based on a Chimpanzee Adenovirus

Journal of Virology ◽

10.1128/jvi.75.23.11603-11613.2001 ◽

2001 ◽

Vol 75 (23) ◽

pp. 11603-11613 ◽

Cited By ~ 189

Author(s):

Steven F. Farina ◽

Guang-ping Gao ◽

Z. Q. Xiang ◽

John J. Rux ◽

Roger M. Burnett ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Human Adenovirus ◽

Adenovirus Type ◽

Open Reading Frames ◽

Hypervariable Regions ◽

293 Cells ◽

Coxsackievirus And Adenovirus Receptor ◽

Cross Neutralization ◽

Adenovirus Receptor ◽

Adenovirus Type 5

ABSTRACT An adenovirus previously isolated from a mesenteric lymph node from a chimpanzee was fully sequenced and found to be similar in overall structure to human adenoviruses. The genome of this virus, called C68, is 36,521 bp in length and is most similar to subgroup E of human adenovirus, with 90% identity in most adenovirus type 4 open reading frames that have been sequenced. Substantial differences in the hexon hypervariable regions were noted between C68 and other known adenoviruses, including adenovirus type 4. Neutralizing antibodies to C68 were highly prevalent in sera from a population of chimpanzees, while sera from humans and rhesus monkeys failed to neutralize C68. Furthermore, infection with C68 was not neutralized from sera of mice immunized with human adenovirus serotypes 2, 4, 5, 7, and 12. A replication-defective version of C68 was created by replacing the E1a and E1b genes with a minigene cassette; this vector was efficiently transcomplemented by the E1 region of human adenovirus type 5. C68 vector transduced a number of human and murine cell lines. This nonhuman adenoviral vector is sufficiently similar to human serotypes to allow growth in 293 cells and transduction of cells expressing the coxsackievirus and adenovirus receptor. As it is dissimilar in regions such as the hexon hypervariable domains, C68 vector avoids significant cross-neutralization by sera directed against human serotypes.

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Identification of novel human adenovirus candidates using the coxsackievirus and adenovirus receptor for cell entry

Virology Journal ◽

10.1186/s12985-020-01318-w ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Kemal Mese ◽

Oskar Bunz ◽

Sebastian Schellhorn ◽

Wolfram Volkwein ◽

Dominik Jung ◽

...

Keyword(s):

Human Adenovirus ◽

Cell Entry ◽

Coxsackievirus And Adenovirus Receptor ◽

Adenovirus Receptor

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144. The Primary Receptor for Adenovirus Serotype 3 (Subgroup B) Has a Unique and Distinct Location on the Cell Surface as Compared to the Coxsackievirus and Adenovirus Receptor

Molecular Therapy ◽

10.1016/s1525-0016(16)40586-1 ◽

2003 ◽

Vol 7 (5) ◽

pp. S57

Keyword(s):

Cell Surface ◽

Adenovirus Serotype ◽

Primary Receptor ◽

Coxsackievirus And Adenovirus Receptor ◽

Adenovirus Receptor

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High resolution STEM imaging study on high Tc superconductor YBa2CuaO7-x

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100106478 ◽

1988 ◽

Vol 46 ◽

pp. 882-883

Author(s):

H.-J. Ou ◽

J. M. Cowley

Keyword(s):

Crystal Structure ◽

High Resolution ◽

Grain Boundary ◽

Strong Field ◽

Imaging Study ◽

Structure Defects ◽

High Tc ◽

High Tc Superconductor ◽

Diffraction Patterns ◽

Lattice Planes

Using the dedicate VG-HB5 STEM microscope, the crystal structure of high Tc superconductor of YBa2Cu3O7-x has been studied via high resolution STEM (HRSTEM) imaging and nanobeam (∽3A) diffraction patterns. Figure 1(a) and 2(a) illustrate the HRSTEM image taken at 10' times magnification along [001] direction and [100] direction, respectively. In figure 1(a), a grain boundary with strong field contrast is seen between two crystal regions A and B. The grain boundary appears to be parallel to a (110) plane, although it is not possible to determine [100] and [001] axes as it is in other regions which contain twin planes [3]. Following the horizontal lattice lines, from left to right across the grain boundary, a lattice bending of ∽4° is noticed. Three extra lattice planes, indicated by arrows, were found to terminate at the grain boundary and form dislocations. It is believed that due to different chemical composition, such structure defects occur during crystal growth. No bending is observed along the vertical lattice lines.

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