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Adenoviruses (members of the family Adenoviridae) are medium-sized (90–100 nanometer), nonenveloped (without an outer lipid bilayer) with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from their initial isolation from human in 1953.
They have a broad range of vertebrate hosts; in humans, more than 50 distinct adenoviral have been found to cause a wide range of illnesses, from mild respiratory infections in young children (the common cold) to life-threatening multi-organ disease in people with a Immunodeficiency.
Different types/serotypes are associated with different conditions:
All these types are called Human mastadenovirus A–G by the ICTV, because all are members of the genus Mastadenovirus.
In 2010, the structure of the human adenovirus was solved at the atomic level, making it the largest high-resolution model ever. The virus is composed of around 1 million amino acid residues and weighs around 150 MDa.
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, which is one of the capsid constituents (see Adenovirus genome) is released from it. (2025). 9781555819330, American Society of Microbiology. ISBN 9781555819330 Protein VI contains an N-terminal amphiphatic alpha-helix, a helical domain that exhibits both hydrophobic and hydrophilic properties. This amphipathic helix enables the binding of protein VI to the endosomal membrane leading to a severe membrane curvature that ultimately disrupts the endosome. 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 Cell nucleus via the nuclear pore. After this the DNA associates with histone molecules already present in the nucleus, which allows it to interact with the host cell transcription machinery. Then, viral gene expression can occur, without integrating the viral genome into host cell chromosomes, 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 Dicistronic 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 replication; 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. E1A is mostly intrinsically disordered protein and contains CR3 domain which is critical for transcriptional activation.
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.
Two types of Canidae 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 and Vulpes lagopus) and may cause hepatitis and encephalitis. Canine adenovirus 2 (CAdV-2) is one of the potential causes of kennel cough. Core for 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 edema was a common complication. (1993). 9780122530562, Academic Press, Inc. ISBN 9780122530562
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.
An adenovirus has been identified as the cause of melanistic hyperpigmentation or “blotchy bass syndrome” in Micropterus.
Adenoviruses are also known to cause respiratory infections in , cattle, , sheep, and . Equine adenovirus 1 can also cause fatal disease in immunocompromised Arabian horse, involving pneumonia and destruction of pancreas and salivary gland tissue. Tupaia adenovirus (TAV) (tree shrew adenovirus 1) has been isolated from tree shrews.
Otarine adenovirus 1 has been isolated from ( Zalophus californianus).
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 (Milvus migrans).
Titi monkey adenovirus was isolated from a colony of monkeys.
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 on 18 October 2011.
Prevention of adenovirus, as well as other respiratory illnesses, involves frequent hand washing for more than 20 seconds, avoiding touching the eyes, face, and nose with unwashed hands, and avoiding close contact with people with symptomatic adenovirus infection. Those with symptomatic adenovirus infection are additionally advised to cough or sneeze into the arm or elbow instead of the hand, to avoid sharing cups and eating utensils, and to refrain from kissing others. Chlorination of swimming pools can prevent outbreaks of conjunctivitis caused by adenovirus.
Some children (especially the youngest) 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 expectoration (e.g. aerosols), but they 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 are not sufficiently chlorinated.
As with many other illnesses, good handwashing practice is one way to inhibit the person-to-person transmission of adenoviruses. Heat and bleach will kill adenoviruses on objects.
A safety issue with adenoviruses is that they can cause an immune response with a related inflammatory response as occurred in the death of Jesse Gelsinger in 1999. To address this risk, the genome of the viral genes have been modified to remove some viral genes. One such modification is the gutless vector that removes almost all the viral genome.
Adenovirus has been used for delivery of CRISPR Gene therapy systems, but high immune reactivity to viral infection has posed challenges in use for patients.
Adenovirus have been used to produce viral vector COVID-19 vaccines. "In four candidate COVID-19 vaccines... Ad5... serves as the 'vector' to transport the surface protein gene of SARS-CoV-2". The goal is to genetically express the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A replication-deficient chimpanzee adenovirus vaccine vector (ChAdOx1) is used by the Oxford–AstraZeneca COVID-19 vaccine that has been approved for use. The Janssen COVID-19 vaccine uses modified recombinant adenovirus type-26 (Ad26). Recombinant adenovirus type-5 (Ad5) are being used by Ad5-nCoV, ImmunityBio and UQ-CSL V451. The Gam-COVID-Vac (aka Sputnik-V) product is innovative because an Ad26 based vaccine is used on the first day and an Ad5 vaccine is used on day 21. Another one is ChAd-SARS-CoV-2-S; the vaccine reportedly prevented mice that were genetically modified to have human ACE2 (hACE2) receptors, presumably receptors that allow virus-entry into the cells, from being infected with SARS-CoV-2.
Possible issues with using Adenovirus as vaccine vectors include: the human body develops immunity to the vector itself, making subsequent booster shots difficult or impossible. In some cases, people have pre-existing immunity to Adenoviruses, making vector delivery ineffective.
By comparison, a Science article reported that China had approved CanSino's Ebola vaccine based on an Ad5 vector. It was tested in Sierra Leone, which had high HIV prevalence, making it more likely for such problems to be detected. CanSino's CEO said "we haven't seen anything with the Ebola vaccine" and speculated that HIV susceptibility might be limited to Ad5 vaccines which produced HIV proteins. In research reported in The Lancet in May, the company's researchers acknowledged the possibility, called it "controversial" and said they would watch for it in the company's COVID-19 vaccine candidate's trials. It is not known to what extent LGBT discrimination in Sierra Leone could have contributed to masking a possible causal link in the Ebola vaccine trial; while the Step trial enrolled mainly homosexual and bisexual men, the Phambili trial enrolled mainly heterosexual men and women and still found an apparent connection.
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