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Adenoviruses (members of the
family Family (from la, familia) is a group of people related either by consanguinity (by recognized birth) or affinity (by marriage or other relationship). The purpose of the family is to maintain the well-being of its members and of society. Idea ...
''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer)
virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsk ...
es with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from their initial isolation from human adenoids in 1953. They have a broad range of
vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
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 Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
.


Virology


Classification

This family contains the following genera: * '' Atadenovirus'' * '' Aviadenovirus'' * '' Ichtadenovirus'' * '' Mastadenovirus'' (including all human adenoviruses) * '' Siadenovirus'' * '' Testadenovirus''


Diversity

In humans, currently there are 88 human adenoviruses (HAdVs) in seven species (Human adenovirus A to G): * 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, 58, 59, 60, 62, 63, 64, 65, 67, 69, 70, 71, 72, 73, 74, 75 * E: 4 * F: 40, 41 * G: 52 Different types/serotypes are associated with different conditions: *
respiratory disease Respiratory diseases, or lung diseases, are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bro ...
(mainly species HAdV-B and C) *
conjunctivitis Conjunctivitis, also known as pink eye, is inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may occur. The ...
(HAdV-B and D) * gastroenteritis (HAdV-F types 40, 41, HAdV-G type 52) *
obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
or adipogenesis (HAdV-A type 31, HAdV-C type 5, HAdV-D types 9, 36, 37) All these types are called Human mastadenovirus A–G by the ICTV, because all are members of the genus '' Mastadenovirus''.


Structure

Adenoviruses are medium-sized (90–100 nm). The
virion A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's ...
s are composed of one linear piece of double-stranded DNA inside an icosahedral
capsid A capsid is the protein shell of a virus, enclosing its genetic material. It consists of several oligomeric (repeating) structural subunits made of protein called protomers. The observable 3-dimensional morphological subunits, which may or ma ...
. 240 hexon proteins make up the bulk of the capsid, while twelve penton bases cap the icosahedron's corners. The penton bases are associated with protruding fibers that aid in attachment to the host
cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...
via the receptor on its surface. 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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
residues and weighs around 150 MDa. *


Genome

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 The dalton or unified atomic mass unit (symbols: Da or u) is a non-SI unit of mass widely used in physics and chemistry. It is defined as of the mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state and at re ...
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 In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
and are able to replicate in the nucleus of
vertebrate Vertebrates () comprise all animal taxa within the subphylum Vertebrata () (chordates with backbones), including all mammals, birds, reptiles, amphibians, and fish. Vertebrates represent the overwhelming majority of the phylum Chordata, with c ...
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 CD46 complement regulatory protein also known as CD46 (cluster of differentiation 46) and Membrane Cofactor Protein is a protein which in humans is encoded by the ''CD46'' gene. CD46 is an inhibitory complement receptor. Gene This gene is fou ...
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 Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of ov ...
polymerization, which facilitates clathrin-mediated endocytosis, and results in virion's entry into the host cell within an
endosome Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
. 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. 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 In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn a ...
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 Life cycle, life-cycle, or lifecycle may refer to: Science and academia *Biological life cycle, the sequence of life stages that an organism undergoes from birth to reproduction ending with the production of the offspring * Life-cycle hypothesis ...
is separated by the DNA replication process into two phases: an early and a late phase. In both phases, a
primary transcript A primary transcript is the single-stranded ribonucleic acid ( RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs ...
that is
alternatively spliced Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
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 DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs ...
; 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 p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often s ...
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 Okazaki fragments are short sequences of DNA nucleotides (approximately 150 to 200 base pairs long in eukaryotes) which are synthesized discontinuously and later linked together by the enzyme DNA ligase to create the lagging strand during DNA ...
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) (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.


Epidemiology


Transmission

Adenoviruses are unusually stable to
chemical A chemical substance is a form of matter having constant chemical composition and characteristic properties. Some references add that chemical substance cannot be separated into its constituent elements by physical separation methods, i.e., w ...
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 and via aerosols (airborne transmission). Research into the molecular mechanisms underlying adenoviral transmission provide empirical evidence in support of the hypothesis that coxsackievirus/adenovirus receptors (CARs) are needed to transport adenoviruses into certain naive/progenitor cell types.


Humans

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

Bat adenovirus TJM (Bt-AdV-TJM) is a novel species of the ''Mastadenovirus'' genus isolated from ''
Myotis The mouse-eared bats or myotises are a diverse and widespread genus (''Myotis'') of bats within the family Vespertilionidae. The noun "''myotis''" itself is a New Latin construction, from the Greek "''muós'' (meaning "mouse") and "''oûs''" (me ...
'' and '' Scotophilus kuhlii'' in China. It is most closely related to the
tree shrew The treeshrews (or tree shrews or banxrings) are small mammals native to the tropical forests of South and Southeast Asia. They make up the entire order Scandentia, which split into two families: the Tupaiidae (19 species, "ordinary" treeshrews ...
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 Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes ( jaundice), poor appetite, vomiting, tiredness, abdominal ...
. 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
vaccine A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified.
s for
dog The dog (''Canis familiaris'' or ''Canis lupus familiaris'') is a domesticated descendant of the wolf. Also called the domestic dog, it is derived from the extinct Pleistocene wolf, and the modern wolf is the dog's nearest living relative. Do ...
s 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
cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical ...
l 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
horse The horse (''Equus ferus caballus'') is a domesticated, one-toed, hoofed mammal. It belongs to the taxonomic family Equidae and is one of two extant subspecies of ''Equus ferus''. The horse has evolved over the past 45 to 55 million yea ...
s,
cattle Cattle (''Bos taurus'') are large, domesticated, cloven-hooved, herbivores. They are a prominent modern member of the subfamily Bovinae and the most widespread species of the genus ''Bos''. Adult females are referred to as cows and adult ma ...
, pigs,
sheep Sheep or domestic sheep (''Ovis aries'') are domesticated, ruminant mammals typically kept as livestock. Although the term ''sheep'' can apply to other species in the genus '' Ovis'', in everyday usage it almost always refers to domesticated ...
, and
goat The goat or domestic goat (''Capra hircus'') is a domesticated species of goat-antelope typically kept as livestock. It was domesticated from the wild goat (''C. aegagrus'') of Southwest Asia and Eastern Europe. The goat is a member of the a ...
s. ''Equine adenovirus 1'' can also cause fatal disease in immunocompromised Arabian foals, involving pneumonia and destruction of
pancreatic The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e. it has both an endocr ...
and
salivary gland The salivary glands in mammals are exocrine glands that produce saliva through a system of ducts. Humans have three paired major salivary glands ( parotid, submandibular, and sublingual), as well as hundreds of minor salivary glands. Salivary ...
tissue. ''Tupaia adenovirus'' (TAV) (tree shrew adenovirus 1) has been isolated from tree shrews. Otarine adenovirus 1 has been isolated from
sea lion Sea lions are pinnipeds characterized by external ear flaps, long foreflippers, the ability to walk on all fours, short and thick hair, and a big chest and belly. Together with the fur seals, they make up the family Otariidae, eared seals. ...
s (''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
black kite The black kite (''Milvus migrans'') is a medium-sized bird of prey in the family Accipitridae, which also includes many other diurnal raptors. It is thought to be the world's most abundant species of Accipitridae, although some populations have ...
s (Milvus migrans).
Titi monkey The titis, or titi monkeys, are New World monkeys of the subfamily Callicebinae, which contains three extant genera: ''Cheracebus'', ''Callicebus'', and ''Plecturocebus.'' This subfamily also contains the extinct genera ''Miocallicebus, Homuncul ...
adenovirus was isolated from a colony of monkeys.


Prevention

Currently there is a vaccine for adenovirus type 4 and 7 for US military personnel only. US 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. 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 on 18 October 2011. More information is available here. 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.


Diagnosis

Diagnosis is from symptoms and history. Tests are only necessary in very serious cases. Tests include blood tests, eyes, nose or throat swabs, stool sample tests, and chest x-rays. In the laboratory, adenovirus can be identified with antigen detection, polymerase chain reaction (PCR), virus isolation and serology. Even if adenovirus is found to be present, it may not be the cause of any symptoms. Some immunocompromised individuals can shed the virus for weeks and show no symptoms.


Infections

Most infections with adenovirus result in infections of the upper respiratory tract. Adenovirus infections often present as
conjunctivitis Conjunctivitis, also known as pink eye, is inflammation of the outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may occur. The ...
, tonsillitis (which may look exactly like
strep throat Streptococcal pharyngitis, also known as streptococcal sore throat (strep throat), is pharyngitis (an infection of the pharynx, the back of the throat) caused by ''Streptococcus pyogenes'' a gram-positive, group A streptococcus. Common sympto ...
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 the youngest) can develop adenovirus
bronchiolitis Bronchiolitis is inflammation of the small airways in the lungs. Acute bronchiolitis is due to a viral infection usually affecting children younger than two years of age. Symptoms may include fever, cough, runny nose, wheezing, and breathing ...
or
pneumonia Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severi ...
, both of which can be severe. In babies, adenoviruses can also cause coughing fits that look almost exactly like
whooping cough Whooping cough, also known as pertussis or the 100-day cough, is a highly contagious bacterial disease. Initial symptoms are usually similar to those of the common cold with a runny nose, fever, and mild cough, but these are followed by two or t ...
. 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.


Treatment

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 Cidofovir, brand name Vistide, is a topical or injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis (an infection of the retina of the eye) in people with AIDS. Cidofovir was approved for medical u ...
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 gene therapy and vaccination


Gene therapy

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 Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment ( pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks ...
, in the form of
recombinant DNA Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be fo ...
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 Adenovirus varieties have been explored extensively as a viral vector for gene therapy and also as an oncolytic virus. Of the many different viruses being explored for oncolytic potential, an adenovirus was the first to be approved by a regulatory ...
is an approved cancer treatment. Specific modifications on fiber proteins are used to target Adenovirus to certain cell types; a major effort is made to limit
hepatotoxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...
and prevent multiple organ failure. Adenovirus dodecahedron can qualify as a potent delivery platform for foreign antigens to human
myeloid dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...
(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.


Vaccines

Modified ( recombinant) adenovirus vectors, including replication incompetent types, can deliver DNA coding for specific
antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
s. 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 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
). A replication-deficient chimpanzee adenovirus vaccine vector (ChAdOx1) is used by the
Oxford–AstraZeneca COVID-19 vaccine The Oxford–AstraZeneca COVID19 vaccine, sold under the brand names Covishield and Vaxzevria among others, is a viral vector vaccine for prevention of COVID-19. Developed in the United Kingdom by Oxford University and British-Swedish com ...
that has been approved for use. The
Janssen COVID-19 vaccine The Janssen COVID19 vaccine, sold under the brand name Jcovden, is a COVID19 vaccine that was developed by Janssen Vaccines in Leiden, Netherlands, and its Belgian parent company Janssen Pharmaceuticals, a subsidiary of American company John ...
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.


HIV infection concerns

The use of Ad5 vaccines for COVID-19 worried researchers who had experience with two failed trials of an Ad5 vaccine, Phambili and STEP, due to the increased risk for uncircumcised male patients of contracting
HIV-1 The subtypes of HIV include two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2). HIV-1 is related to viruses found in chimpanzees and gorillas living in western Africa, while HIV-2 viruses are related to viruses found in the sooty mangabey ...
via unprotected anal sex. At the time, it was concluded that heightened risk of HIV reception may be observed for any Ad5-based vector vaccine. In October 2020, these researchers wrote in ''
The Lancet ''The Lancet'' is a weekly peer-reviewed general medical journal and one of the oldest of its kind. It is also the world's highest-impact academic journal. It was founded in England in 1823. The journal publishes original research articles, ...
'': "On the basis of these findings, we are concerned that use of an Ad5 vector for immunisation against SARS-CoV-2 could similarly increase the risk of HIV-1 acquisition among men who receive the vaccine." Vaccines using other technologies would not be affected, but Sputnik V, Convidecia and ImmunityBio's hAd5 would. Two studies found that Ad5-specific CD4
T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s are more susceptible to HIV infection than CD4 T cells specific to certain other vectors, such as Cytomegalovirus and
Canarypox Canarypox virus (CNPV) is an ''Avipoxvirus'' and etiologic agent of canarypox, a disease of wild and captive birds that can cause significant losses. Canarypox can enter human cells, but it cannot survive and multiply in human cells. There is a ...
. By comparison, a ''
Science Science is a systematic endeavor that Scientific method, builds and organizes knowledge in the form of Testability, testable explanations and predictions about the universe. Science may be as old as the human species, and some of the earli ...
'' article reported that China had approved CanSino's Ebola vaccine based on an Ad5 vector. It was tested in
Sierra Leone Sierra Leone,)]. officially the Republic of Sierra Leone, is a country on the southwest coast of West Africa. It is bordered by Liberia to the southeast and Guinea surrounds the northern half of the nation. Covering a total area of , Sierr ...
, which had high HIV
prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number o ...
, 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.


See also

* VA (viral associated) RNA


References


External links


Centers for Disease Control and Prevention—National Center for Diseases—Division of Viral and Rickettsial Diseases
Respiratory and Enteric Viruses Branch






General information on Adenovirus



Sequenced adenoviruses





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

ICTV
{{Authority control Virus families