Adenoviridae

Adenoviruses
Transmission electron micrograph of two adenovirus particles
Virus classification
Group: Group I (dsDNA)
Order: Unassigned
Family: Adenoviridae
Genera

Adenoviruses (members of the family Adenoviridae) are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double stranded DNA genome. Their name derives from their initial isolation from human adenoids in 1953.[1]

They have a broad range of vertebrate hosts; in humans, more than 50 distinct adenoviral serotypes have been found to cause a wide range of illnesses, from mild respiratory infections in young children (known as the common cold) to life-threatening multi-organ disease in people with a weakened immune system.

Virology

Taxonomy

Group: dsDNA

[2]

Classification

This family contains the following genera:

Diversity

Classification of Adenoviridae can be complex.

In humans, there are 57 accepted human adenovirus types (HAdV-1 to 57) in seven species (Human adenovirus A to G):[3]

Different types/serotypes are associated with different conditions:

When not restricting the subject to human viruses, Adenoviridae can be divided into five genera: Mastadenovirus, Aviadenovirus, Atadenovirus, Siadenovirus, and Ichtadenovirus.[3]

Structure

Adenoviruses represent the largest nonenveloped viruses. They are able to be transported through the endosome (i.e., envelope fusion is not necessary). The virion also has a unique "spike" or fiber associated with each penton base of the capsid (see picture below) that aids in attachment to the host cell via the receptor on the surface of the host cell. (See Replication Section below for discussion of diverse receptors.)

In 2010, scientists announced that they had solved the structure of the human adenovirus at the atomic level, making the largest high-resolution model ever. The virus is composed of around 1 million amino acid residues and weighs around 150 MDa.[8][9]

Genome

Main article: Adenovirus genome
Schematic diagram of the linear adenovirus genome, showing Early genes (E) and Late genes (L).

The adenovirus genome is linear, non-segmented double-stranded (ds) DNA that is between 26 and 48 Kbp. This allows the virus to theoretically carry 22 to 40 genes. Although this is significantly larger than other viruses in its Baltimore group, it is still a very simple virus and is heavily reliant on the host cell for survival and replication. An interesting feature of this viral genome is that it has a terminal 55 kDa protein associated with each of the 5' ends of the linear dsDNA. These are used as primers in viral replication and ensure that the ends of the virus' linear genome are adequately replicated.

Replication

Adenoviruses possess a linear dsDNA genome and are able to replicate in the nucleus of vertebrate cells using the host’s replication machinery.

The structure of adenovirus. 1 = penton capsomeres 2 = hexon capsomeres, and 3= viral genome (linear dsDNA)

Entry of adenoviruses into the host cell involves two sets of interactions between the virus and the host cell. Most of the action occurs at the vertices. Entry into the host cell is initiated by the knob domain of the fiber protein binding to the cell receptor. The two currently established receptors are: CD46 for the group B human adenovirus serotypes and the coxsackievirus adenovirus receptor (CAR) for all other serotypes. There are some reports suggesting MHC molecules and sialic acid residues functioning in this capacity as well. This is followed by a secondary interaction, where a motif in the penton base protein interacts with an integrin molecule. It is the co-receptor interaction that stimulates entry of the adenovirus. This co-receptor molecule is αv integrin. Binding to αv integrin results in endocytosis of the virus particle via clathrin-coated pits. Attachment to αv integrin stimulates cell signaling and thus induces actin polymerization resulting in entry of the virion into the host cell within an endosome.[10]

Once the virus has successfully gained entry into the host cell, the endosome acidifies, which alters virus topology by causing capsid components to disband. These changes, as well as the toxic nature of the pentons, destroy the endosome, resulting in the movement of the virion into the cytoplasm. With the help of cellular microtubules, the virus is transported to the nuclear pore complex, whereby the adenovirus particle disassembles. Viral DNA is subsequently released, which can enter the nucleus via the nuclear pore.[11] After this the DNA associates with histone molecules. Thus, viral gene expression can occur and new virus particles can be generated.

The adenovirus life cycle is separated by the DNA replication process into two phases: an early and a late phase. In both phases, a primary transcript that is alternatively spliced to generate monocistronic mRNAs compatible with the host’s ribosome is generated, allowing for the products to be translated.

The early genes are responsible for expressing mainly non-structural, regulatory proteins. The goal of these proteins is threefold: to alter the expression of host proteins that are necessary for DNA synthesis; to activate other virus genes (such as the virus-encoded DNA polymerase); and to avoid premature death of the infected cell by the host-immune defenses (blockage of apoptosis, blockage of interferon activity, and blockage of MHC class I translocation and expression).

Some adenoviruses under specialized conditions can transform cells using their early gene products. E1A (binds Retinoblastoma tumor suppressor protein) has been found to immortalize primary cells in vitro allowing E1B (binds p53 tumor suppressor) to assist and stably transform the cells. Nevertheless, they are reliant upon each other to successfully transform the host cell and form tumors.

DNA replication separates the early and late phases. Once the early genes have liberated adequate virus proteins, replication machinery, and replication substrates, replication of the adenovirus genome can occur. A terminal protein that is covalently bound to the 5’ end of the adenovirus genome acts as a primer for replication. The viral DNA polymerase then uses a strand displacement mechanism, as opposed to the conventional Okazaki fragments used in mammalian DNA replication, to replicate the genome.

The late phase of the adenovirus lifecycle is focused on producing sufficient quantities of structural protein to pack all the genetic material produced by DNA replication. Once the viral components have successfully been replicated, the virus is assembled into its protein shells and released from the cell as a result of virally induced cell lysis.

Multiplicity reactivation

Adenovirus is capable of multiplicity reactivation (MR)[12] (Yamamoto and Shimojo, 1971). MR is the process by which two, or more, virus genomes containing lethal damage interact within the infected cell to form a viable virus genome. Such MR was demonstrated for adenovirus 12 after virions were irradiated with UV light and allowed to undergo multiple infection of host cells.[12] In a review, numerous examples of MR in different viruses were described, and it was suggested that MR is a common form of sexual interaction that provides the survival advantage of recombinational repair of genome damages.[13]

Epidemiology

Transmission

Adenoviruses are unusually stable to chemical or physical agents and adverse pH conditions, allowing for prolonged survival outside of the body and water. Adenoviruses are spread primarily via respiratory droplets, however they can also be spread by fecal routes. Research into the molecular mechanisms underlying adenoviral transmission provide empirical evidence in support of the hypothesis that cellular receptors for adenovirus and coxsackievirus (CARs) are needed to transport adenoviruses into certain naive/progenitor cell types.[14]

Humans

Main article: Adenovirus infection

Humans infected with adenoviruses display a wide range of responses, from no symptoms at all to the severe infections typical of Adenovirus serotype 14.

Animals

See also: DA2PPC Vaccine

Bat adenovirus TJM (Bt-AdV-TJM) is a novel species of the Mastadenovirus genus isolated from Myotis and Scotophilus kuhlii in China.[15] It is a double stranded DNA virus with no RNA sequence. It is most closely related to the tree shrew and canine AdVs.[16]

Two types of canine adenoviruses are well known, type 1 and 2. Type 1 causes infectious canine hepatitis, a potentially fatal disease involving vasculitis and hepatitis. Type 1 infection can also cause respiratory and eye infections. Canine adenovirus 2 (CAdV-2) is one of the potential causes of kennel cough. Core vaccines for dogs include attenuated live CAdV-2, which produces immunity to CAdV-1 and CAdV-2. CAdV-1 was initially used in a vaccine for dogs, but corneal edema was a common complication.[17]

Adenovirus in Reptiles is poorly understood, but research is currently in progress.

Adenoviruses are also known to cause respiratory infections in horses, cattle, pigs, sheep, and goats. Equine adenovirus 1 can also cause fatal disease in immunocompromised Arabian foals, involving pneumonia and destruction of pancreatic and salivary gland tissue.[17] Tupaia adenovirus (TAV) (Tree shrew adenovirus 1) has been isolated from tree shrews.

Otarine adenovirus 1 has been isolated from sea lions.[18]

The Fowl adenoviruses are associated with many disease conditions in domestic fowl like Inclusion body hepatitis, Hydropericardium syndrome, Egg drop syndrome, Quail bronchitis and many respiratory conditions.They have also been isolated from wild kites (Milvus migrans).[19]

Titi monkey adenovirus was isolated from a colony of monkeys.[20]

Prevention

Main article: Adenovirus vaccine

In the past, US military recruits were vaccinated against two serotypes of adenotypes, with a corresponding decrease in illnesses caused by those serotypes. That vaccine is no longer manufactured. The U.S. Army Medical Research and Materiel Command announced on 31 October 2011 that a new adenovirus vaccine, which replaces the older version that has been out of production for over a decade, was shipped to basic training sites Oct. 18, 2011. More information is available here.

Good hygiene, including handwashing, is still the best way to avoid picking up the adenovirus from an infected person.

Infections

Main article: Adenovirus infection

Most infections with adenovirus result in infections of the upper respiratory tract. Adenovirus infections often show up as conjunctivitis, tonsilitis (which may look exactly like strep throat and cannot be distinguished from strep except by throat culture), an ear infection, or croup. Adenoviruses, types 40 and 41 can also cause gastroenteritis.[21] A combination of conjunctivitis and tonsilitis is particularly common with adenovirus infections. Some children (especially small ones) can develop adenovirus bronchiolitis or pneumonia, both of which can be severe. In babies, adenoviruses can also cause coughing fits that look almost exactly like whooping cough. Adenoviruses can also cause viral meningitis or encephalitis. Rarely, adenovirus can cause hemorrhagic cystitis (inflammation of the urinary bladder—a form of urinary tract infection — with blood in the urine).

Most people recover from adenovirus infections by themselves, but people with immunodeficiency sometimes die of adenovirus infections, and — rarely — even previously healthy people can die of these infections.[22]

Adenoviruses are often transmitted by expectorate, but can also be transmitted by contact with an infected person, or by virus particles left on objects such as towels and faucet handles. Some people with adenovirus gastroenteritis may shed the virus in their stools for months after getting over the symptoms. The virus can be passed through water in swimming pools that do not have enough chlorine in them. As with many other illnesses, good handwashing is one way to inhibit the spread of adenoviruses from one person to another. Heat and bleach will kill adenoviruses on objects.

Treatment

There are no antiviral drugs to treat adenoviral infections, so treatment is largely directed at the symptoms (such as acetaminophen for fever). A doctor may give antibiotic eyedrops for conjunctivitis, since it takes a while to test to see if the eye infection is bacterial or viral and to help prevent secondary bacterial infections. Currently, there is no adenovirus vaccine available to the general public, but a vaccine is available for the United States military for Types 4 and 7.

Use in treatment of unrelated diseases

Adenoviruses have long been a popular viral vector for gene therapy due to their ability to affect both replicating and non-replicating cells, accommodate large transgenes, and code for proteins without integrating into the host cell genome. More specifically they’re used as a vehicle to administer targeted therapy,[23] in the form of recombinant DNA or protein. This therapy has been found especially useful in treating cystic fibrosis. Specific modifications on fibre proteins are used to target Adenovirus to certain cell types;[24] a major effort is made to limit hepatotoxicity and prevent multiple organ failure. Adenovirus dodecahedron can qualify as a potent delivery platform for foreign antigens to human myeloid dendritic cells (MDC), and that it is efficiently presented by MDC to M1-specific CD8+ T lymphocytes.[25]

In China, oncolytic adenovirus is an approved cancer treatment.[26]

References

  1. ↑ Rowe WP, Huebner RJ, Gilmore LK, Parrott RH, Ward TG (December 1953). "Isolation of a cytopathogenic agent from human adenoids undergoing spontaneous degeneration in tissue culture". Proc. Soc. Exp. Biol. Med. 84 (3): 570–573. doi:10.3181/00379727-84-20714. PMID 13134217.
  2. ↑ ICTV. "Virus Taxonomy: 2014 Release". Retrieved 15 June 2015.
  3. 1 2 Martin, Malcolm A.; Knipe, David M.; Fields, Bernard N.; Howley, Peter M.; Griffin, Diane; Lamb, Robert (2007). Fields' virology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 2395. ISBN 0-7817-6060-7.
  4. ↑ Walsh, M. P.; Seto, J.; Liu, E. B.; Dehghan, S.; Hudson, N. R.; Lukashev, A. N.; Ivanova, O.; Chodosh, J.; Dyer, D.; Jones, M. S.; Seto, D. (2011). "Computational analysis of two species C human adenoviruses provides evidence of a novel virus". Journal of Clinical Microbiology 49 (10): 3482–3490. doi:10.1128/JCM.00156-11. PMC 3187342. PMID 21849694.
  5. ↑ Robinson, C. M.; Singh, G.; Henquell, C. C.; Walsh, M. P.; Peigue-Lafeuille, H. L. N.; Seto, D.; Jones, M. S.; Dyer, D. W.; Chodosh, J. (2011). "Computational analysis and identification of an emergent human adenovirus pathogen implicated in a respiratory fatality". Virology 409 (2): 141–147. doi:10.1016/j.virol.2010.10.020. PMC 3006489. PMID 21056888.
  6. ↑ Jones, M. S.; Harrach, B.; Ganac, R. D.; Gozum, M. M. A.; Dela Cruz, W. P.; Riedel, B.; Pan, C.; Delwart, E. L.; Schnurr, D. P. (2007). "New Adenovirus Species Found in a Patient Presenting with Gastroenteritis". Journal of Virology 81 (11): 5978–5984. doi:10.1128/JVI.02650-06. PMC 1900323. PMID 17360747.
  7. ↑ Voss, Jameson D.; Atkinson, Richard L.; Dhurandhar, Nikhil V. (2015). "Role of adenoviruses in obesity". Medical Virology 25 (6): 379–387. doi:10.1002/rmv.1852. PMID 26352001.
  8. ↑ Scientists Unveil Structure of Adenovirus, the Largest High-Resolution Complex Ever Found Science Daily website, retrieved August 30, 2010
  9. ↑ Harrison, S. C. (2010). "Virology. Looking inside adenovirus". Science 329 (5995): 1026–1027. Bibcode:2010Sci...329.1026H. doi:10.1126/science.1194922. PMID 20798308.
  10. ↑ Wu E, Nemerow GR (2004). "Virus yoga: the role of flexibility in virus host cell recognition". Trends Microbiol 12 (4): 162–168. doi:10.1016/j.tim.2004.02.005. PMID 15051066.
  11. ↑ Meier O, Greber UF (2004). "Adenovirus endocytosis". J Gene Med 6 (Suppl 1): S152–S163. doi:10.1002/jgm.553. PMID 14978758.
  12. 1 2 Yamamoto H, Shimojo H (August 1971). "Multiplicity reactivation of human adenovirus type 12 and simian virus 40 irradiated by ultraviolet light". Virology 45 (2): 529–31. doi:10.1016/0042-6822(71)90355-2. PMID 4328814.
  13. ↑ Michod RE, Bernstein H, Nedelcu AM (2008). "Adaptive value of sex in microbial pathogens" (PDF). Infect Genet Evol 8 (3): 267–285. doi:10.1016/j.meegid.2008.01.002. PMID 18295550.
  14. ↑ Wan et al and DeGregori. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13784-9
  15. ↑ Chen, LH; Wu, ZQ; Hu, YF; et al. (2012). "Genetic diversity of adenoviruses in bats in China". Bing Du Xue Bao. 4: 403–8.
  16. ↑ Li, Y; Ge, X; Zhang, H; Zhou, P; Zhu, Y; Zhang, Y; Yuan, J; Wang, LF; Shi, Z (Apr 2010). "Host range, prevalence, and genetic diversity of adenoviruses in bats". J Virol 84 (8): 3889–97. doi:10.1128/JVI.02497-09.
  17. 1 2 Fenner, Frank J.; Gibbs, E. Paul J.; Murphy, Frederick A.; Rott, Rudolph; Studdert, Michael J.; White, David O. (1993). Veterinary Virology (2nd ed.). Academic Press, Inc. ISBN 0-12-253056-X.
  18. ↑ Goldstein, T.; Colegrove, K. M.; Hanson, M.; Gulland, F. M. D. (2011). "Isolation of a novel adenovirus from California sea lions Zalophus californianus". Diseases of Aquatic Organisms 94 (3): 243–248. doi:10.3354/dao02321. PMID 21790072.
  19. ↑ Kumar, R.; Kumar, V.; Asthana, M.; Shukla, S. K.; Chandra, R. (2010). "Isolation and identification of a fowl adenovirus from wild Black Kites (Milvus migrans)". Journal of wildlife diseases 46 (1): 272–276. doi:10.7589/0090-3558-46.1.272. PMID 20090043.
  20. ↑ Chen, E. C.; Yagi, S.; Kelly, K. R.; Mendoza, S. P.; Tarara, N.; Canfield, A.; Maninger, A.; Rosenthal, K. L.; Spinner, D. P.; Bales, K. L.; Schnurr, D. P.; Lerche, N. W.; Chiu, C. Y. (2011). Nemerow, Glen R, ed. "Cross-Species Transmission of a Novel Adenovirus Associated with a Fulminant Pneumonia Outbreak in a New World Monkey Colony". PLoS Pathogens 7 (7): e1002155. doi:10.1371/journal.ppat.1002155. PMC 3136464. PMID 21779173.
  21. ↑ Wadell G.; et al. (1987). Whelan, Julie; Bock, Gregory, ed. Novel diarrhoea viruses. New York: Wiley. p. 63. ISBN 0-471-91094-5.
  22. ↑ Amy Burkholder (2007-12-19). "A killer cold? Even the healthy may be vulnerable". CNN. Retrieved 2007-12-19.
  23. ↑ Thacker, E. E.; Nakayama, M.; Smith, B. F.; Bird, R. C.; Muminova, Z.; Strong, T. V.; Timares, L.; Korokhov, N.; O'Neill, A. M.; De Gruijl, T. D.; Glasgow, J. N.; Tani, K.; Curiel, D. T. (2009). "A genetically engineered adenovirus vector targeted to CD40 mediates transduction of canine dendritic cells and promotes antigen-specific immune responses in vivo". Vaccine 27 (50): 7116–7124. doi:10.1016/j.vaccine.2009.09.055. PMC 2784276. PMID 19786146.
  24. ↑ Xin, K. Q.; Sekimoto, Y.; Takahashi, T.; Mizuguchi, H.; Ichino, M.; Yoshida, A.; Okuda, K. (2007). "Chimeric adenovirus 5/35 vector containing the clade C HIV gag gene induces a cross-reactive immune response against HIV". Vaccine 25 (19): 3809–3815. doi:10.1016/j.vaccine.2007.01.117. PMID 17386962.
  25. ↑ Naskalska, A.; Szolajska, E.; Chaperot, L.; Angel, J.; Plumas, J.; Chroboczek, J. (2009). "Influenza recombinant vaccine: Matrix protein M1 on the platform of the adenovirus dodecahedron". Vaccine 27 (52): 7385–7393. doi:10.1016/j.vaccine.2009.09.021. PMID 19766576.
  26. ↑ Pandha, K. J. Harrington ; edited by Richard G. Vile, Hardev (2008). Viral therapy of cancer. Hoboken, N.J.: Wiley. pp. 1–13. ISBN 9780470019221.

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