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.
|Transmission electron micrograph of two adenovirus particles|
|Virus classification |
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.
This family contains the following genera:
- Genus Atadenovirus; type species: Ovine atadenovirus D
- Genus Aviadenovirus; type species: Fowl aviadenovirus A
- Genus Ichtadenovirus; type species: Sturgeon ichtadenovirus A
- Genus Mastadenovirus (including all human adenoviruses); type species: Human mastadenovirus C
- Genus Siadenovirus; type species: Frog siadenovirus A
Classification of Adenoviridae can be complex.
- A: 12, 18, 31
- B: 3, 7, 11, 14, 16, 21, 34, 35, 50, 55
- C: 1, 2, 5, 6, 57
- D: 8, 9, 10, 13, 15, 17, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 32, 33, 36, 37, 38, 39, 42, 43, 44, 45, 46, 47, 48, 49, 51, 53, 54, 56
- E: 4
- F: 40, 41
- G: 52
Different types/serotypes are associated with different conditions:
- respiratory disease (mainly species HAdV-B and C)
- conjunctivitis (HAdV-B and D)
- gastroenteritis (HAdV-F types 40, 41, HAdV-G type 52)
- obesity or adipogenesis (HAdV-A type 31, HAdV-C type 5, HAdV-D types 9, 36, 37)
Adenoviruses represent the largest known 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.
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.
Adenoviruses possess a linear dsDNA genome and are able to replicate in the nucleus of vertebrate cells using the host's replication machinery.
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 (see capsomere) 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.
Once the virus has successfully gained entry into the host cell, the endosome acidifies, which alters virus topology by causing capsid components to disband. The capsid is destabilized and protein VI is released from the capsid. 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. 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.
Adenovirus is capable of multiplicity reactivation (MR) (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. 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.
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.
Humans infected with adenoviruses display a wide range of responses, from no symptoms at all to the severe infections typical of Adenovirus serotype 14.
Bat adenovirus TJM (Bt-AdV-TJM) is a novel species of the Mastadenovirus genus isolated from Myotis and Scotophilus kuhlii in China. It is a double stranded DNA virus with no RNA sequence. It is most closely related to the tree shrew and canine AdVs.
Two types of canine adenoviruses are well known, type 1 and 2. Type 1 (CAdV-1) causes infectious canine hepatitis, a potentially fatal disease involving vasculitis and hepatitis. Type 1 infection can also cause respiratory and eye infections. CAdV-1 also affects foxes (Vulpes vulpes, Vulpes lagopus) and may cause except hepatitis also encephalitis. 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.
Squirrel adenovirus (SqAdV) is reported to cause enteritis in red squirrels in Europe, while gray squirrels seem to be resistant. SqAdV is most closely related to the adenovirus of guinea pigs (GpAdV).
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. Tupaia adenovirus (TAV) (Tree shrew adenovirus 1) has been isolated from tree shrews.
The Fowl adenoviruses are associated with many disease conditions in domestic fowl like Inclusion body hepatitis, Hydropericardium syndrome, Egg drop syndrome, Quail bronchitis, Gizzard erosions and many respiratory conditions. They have also been isolated from wild Black Kites (Milvus migrans).
Currently, there is a vaccine for adenovirus type 4 and 7 for military personnel only. Military personnel are the recipients of this vaccine because they may be at a higher risk of infection. The vaccine contains a live virus, which may be shed in stool and lead to transmission. There is currently no adenovirus vaccine for the general public. The vaccine is not approved for use outside of the military, as it has not been tested in studied in the general population or on people with weakened immune systems.
In the past, US military recruits were vaccinated against two serotypes of adenovirus, 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.
Prevention of adenovirus, as well as other respiratory illnesses, only requires following a few simple steps: washing your hands often and for more than 20 seconds, avoiding touching your eyes, face, and nose with unwashed hands, and avoiding close contact with those who are sick. If you are already sick, there are ways to keep those around you healthy. This includes staying home and resting, coughing or sneezing into your arm or elbow instead of your hand, not sharing cups and eating utensils with others, refraining from kissing others, and frequently washing your hands for more than 20 seconds.
Healthcare providers will often ask about symptoms and health history. Tests are only necessary for individuals with a very serious case. Tests include blood tests, swabbing the eyes, nose or throat, stool sample testing, or receiving a chest x-ray. In the laboratory, adenovirus can be identified with antigen detection, polymerase chain reaction (PCR), virus isolation and serology. However, even if a person has a positive result for adenovirus, it does not mean it is causing a person's particular illness. Some immunocompromised individuals can shed the virus for weeks and show no symptoms.
Most infections with adenovirus result in infections of the upper respiratory tract. Adenovirus infections often show up as conjunctivitis, tonsillitis (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. A combination of conjunctivitis and tonsillitis 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. This may be because sometimes adenoviral infection can lead to cardiac disorders. For example, in one study, some cardiac samples of patients with dilated cardiomyopathy were positive for presence of adenovirus type 8.
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.
There are no proven antiviral drugs to treat adenoviral infections, so treatment is largely directed at the symptoms (such as acetaminophen for fever). The antiviral drug cidofovir has helped certain of those patients who had severe cases of illness; the number helped and to what degree, and the particular complications or symptoms it helped with, and when and where this happened, were not given in the source. A doctor may give antibiotic eyedrops for conjunctivitis, while awaiting results of bacterial cultures, 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 are used as a vehicle to administer targeted therapy, in the form of recombinant DNA or protein. This therapy has been found especially useful in treating monogenic disease (e.g. cystic fibrosis, X-linked SCID, alpha1-antitrypsin deficiency) and cancer. In China, oncolytic adenovirus is an approved cancer treatment. Specific modifications on fibre proteins are used to target Adenovirus to certain cell types; 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.
Adenovirus has been used for delivery of CRISPR/Cas9 gene editing systems, but high immune reactivity to viral infection has posed challenges in use for patients. Use of adeno-associated virus (AAV) shows promise in overcoming immunogenicity, though it has a smaller payload capacity.
- VA (viral associated) RNA
- 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". Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine. 84 (3): 570–3. doi:10.3181/00379727-84-20714. PMID 13134217.
- ICTV. "Virus Taxonomy: 2014 Release". Retrieved 15 June 2015.
- 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 978-0-7817-6060-7.
- Walsh MP, Seto J, Liu EB, Dehghan S, Hudson NR, Lukashev AN, Ivanova O, Chodosh J, Dyer DW, Jones MS, Seto D (October 2011). "Computational analysis of two species C human adenoviruses provides evidence of a novel virus". Journal of Clinical Microbiology. 49 (10): 3482–90. doi:10.1128/JCM.00156-11. PMC 3187342. PMID 21849694.
- Robinson CM, Singh G, Henquell C, Walsh MP, Peigue-Lafeuille H, Seto D, Jones MS, Dyer DW, Chodosh J (January 2011). "Computational analysis and identification of an emergent human adenovirus pathogen implicated in a respiratory fatality". Virology. 409 (2): 141–7. doi:10.1016/j.virol.2010.10.020. PMC 3006489. PMID 21056888.
- Jones MS, Harrach B, Ganac RD, Gozum MM, Dela Cruz WP, Riedel B, Pan C, Delwart EL, Schnurr DP (June 2007). "New adenovirus species found in a patient presenting with gastroenteritis". Journal of Virology. 81 (11): 5978–84. doi:10.1128/JVI.02650-06. PMC 1900323. PMID 17360747.
- Voss JD, Atkinson RL, Dhurandhar NV (November 2015). "Role of adenoviruses in obesity". Reviews in Medical Virology. 25 (6): 379–87. doi:10.1002/rmv.1852. PMID 26352001.
- Scientists Unveil Structure of Adenovirus, the Largest High-Resolution Complex Ever Found Science Daily website, retrieved August 30, 2010
- Harrison SC (August 2010). "Virology. Looking inside adenovirus". Science. 329 (5995): 1026–7. Bibcode:2010Sci...329.1026H. doi:10.1126/science.1194922. PMID 20798308.
- Wu E, Nemerow GR (April 2004). "Virus yoga: the role of flexibility in virus host cell recognition". Trends in Microbiology. 12 (4): 162–9. doi:10.1016/j.tim.2004.02.005. PMID 15051066.
- Flint J, Skalka AM, Rall GF, Racaniello VR (2015). Principles of Virology. Volume I: Molecular Biology. doi:10.1128/9781555818951. ISBN 9781555819330.
- Meier O, Greber UF (February 2004). "Adenovirus endocytosis". The Journal of Gene Medicine. 6 Suppl 1 (Suppl 1): S152–63. doi:10.1002/jgm.553. PMID 14978758.
- 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.
- Michod RE, Bernstein H, Nedelcu AM (May 2008). "Adaptive value of sex in microbial pathogens" (PDF). Infection, Genetics and Evolution. 8 (3): 267–85. doi:10.1016/j.meegid.2008.01.002. PMID 18295550.
- Wan et al and DeGregori. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13784-9
- Chen LH, Wu ZQ, Hu YF, Yang F, Yang J, Jin Q (June 2012). "[Genetic diversity of adenoviruses in bats of China]". Bing du Xue Bao = Chinese Journal of Virology. 28 (4): 403–8. PMID 22978165.
- Li Y, Ge X, Zhang H, Zhou P, Zhu Y, Zhang Y, Yuan J, Wang LF, Shi Z (April 2010). "Host range, prevalence, and genetic diversity of adenoviruses in bats". Journal of Virology. 84 (8): 3889–97. doi:10.1128/JVI.02497-09. PMC 2849498. PMID 20089640.
- 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 978-0-12-253056-2.
- Goldstein T, Colegrove KM, Hanson M, Gulland FM (May 2011). "Isolation of a novel adenovirus from California sea lions Zalophus californianus". Diseases of Aquatic Organisms. 94 (3): 243–8. doi:10.3354/dao02321. PMID 21790072.
- Kumar R, Kumar V, Asthana M, Shukla SK, Chandra R (January 2010). "Isolation and identification of a fowl adenovirus from wild Black Kites (Milvus migrans)". Journal of Wildlife Diseases. 46 (1): 272–6. doi:10.7589/0090-3558-46.1.272. PMID 20090043.
- Chen EC, Yagi S, Kelly KR, Mendoza SP, Tarara RP, Canfield DR, Maninger N, Rosenthal A, Spinner A, Bales KL, Schnurr DP, Lerche NW, Chiu CY (July 2011). Nemerow GR (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.
- Wadell G.; et al. (1987). Whelan, Julie; Bock, Gregory (eds.). Novel diarrhoea viruses. New York: Wiley. p. 63. ISBN 978-0-471-91094-7.
- Amy Burkholder (2007-12-19). "A killer cold? Even the healthy may be vulnerable". CNN. Retrieved 2007-12-19.
- Hosseini SM, Mirhosseini SM, Taghian M, Salehi M, Farahani MM, Bakhtiari F, Ghasemi-Pirbaluti M, Motaghi E (October 2018). "First evidence of the presence of adenovirus type 8 in myocardium of patients with severe idiopathic dilated cardiomyopathy". Archives of Virology. 163 (10): 2895–2897. doi:10.1007/s00705-018-3942-3. PMID 30022238.
- Fox, Maggie (January 28, 2018). "Adenovirus looks like flu, acts like flu, but it's not influenza". NBC News.
- Lee CS, Bishop ES, Zhang R, Yu X, Farina EM, Yan S, Zhao C, Zheng Z, Shu Y, Wu X, Lei J, Li Y, Zhang W, Yang C, Wu K, Wu Y, Ho S, Athiviraham A, Lee MJ, Wolf JM, Reid RR, He TC (June 2017). "Adenovirus-Mediated Gene Delivery: Potential Applications for Gene and Cell-Based Therapies in the New Era of Personalized Medicine". Genes & Diseases. 4 (2): 43–63. doi:10.1016/j.gendis.2017.04.001. PMC 5609467. PMID 28944281.
- Thacker EE, Nakayama M, Smith BF, Bird RC, Muminova Z, Strong TV, Timares L, Korokhov N, O'Neill AM, de Gruijl TD, Glasgow JN, Tani K, Curiel DT (November 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): 7116–24. doi:10.1016/j.vaccine.2009.09.055. PMC 2784276. PMID 19786146.
- Pandha, K. J. Harrington; edited by Richard G. Vile, Hardev (2008). Viral therapy of cancer. Hoboken, N.J.: Wiley. pp. 1–13. ISBN 9780470019221.
- Xin KQ, Sekimoto Y, Takahashi T, Mizuguchi H, Ichino M, Yoshida A, Okuda K (May 2007). "Chimeric adenovirus 5/35 vector containing the clade C HIV gag gene induces a cross-reactive immune response against HIV". Vaccine. 25 (19): 3809–15. doi:10.1016/j.vaccine.2007.01.117. PMID 17386962.
- Naskalska A, Szolajska E, Chaperot L, Angel J, Plumas J, Chroboczek J (December 2009). "Influenza recombinant vaccine: matrix protein M1 on the platform of the adenovirus dodecahedron". Vaccine. 27 (52): 7385–93. doi:10.1016/j.vaccine.2009.09.021. PMID 19766576.
- Centers for Disease Control and Prevention—National Center for Diseases—Division of Viral and Rickettsial Diseases, Respiratory and Enteric Viruses Branch
- MicrobiologyBytes: Adenoviruses
- Stanford University—Adenoviruses
- Adenoviruses General Concepts
- General information on Adenovirus
- DNA virus replication strategies
- Sequenced adenoviruses
- Kids Health—Adenoviruses
- Viralzone: Adenoviridae
- Adenovirus Research Discussion Group
- USAMRMC protects Soldiers against unseen enemy
- 3D macromolecular structures of Adenoviruses archived in the EM Data Bank(EMDB)
- Molecule of the Month: Adenovirus