The enzootic nasal tumor virus of the

betaretrovirus ''Betaretrovirus'' is a genus of the ''Retroviridae'' family. It has type B or type D morphology. The type B is common for a few exogenous, vertically transmitted and endogenous viruses of mice; some primate and sheep viruses are the type D. Ex ...

genus is a carcinogenic

retrovirus A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase ...

that causes enzootic nasal adenocarcinoma in sheep and goats. Strain ENTV-1 is found in sheep and strain ENTV-2 is found in goats. The virus causes

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

growth in the upper nasal cavity and is closely related to JSRV which also causes respiratory tumors in

ovine 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 s ...

. The disease, enzootic nasal adenocarcinoma is common in North America and is found in sheep and goats on every continent except

New Zealand New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island count ...

and

Australia Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...

. There are more than 27 betaretroviruses similar to ENVT and JSRV in the ovine genome. In the future, research on ENTV may become important in studying viruses that cause human

lung cancer Lung cancer, also known as lung carcinoma (since about 98–99% of all lung cancers are carcinomas), is a malignant lung tumor characterized by uncontrolled cell growth in tissue (biology), tissues of the lung. Lung carcinomas derive from tran ...

Classification

ENTV belongs to the family ''

Retroviridae A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase e ...

'', to the subfamily ''

Orthoretrovirinae ''Orthoretrovirinae'' is a subfamily of viruses belonging to ''Retroviridae'', a family of enveloped viruses that replicate in a host cell through the process of reverse transcription. The subfamily currently includes six genera, of which ''Lent ...

'' and the genus ''

Betaretrovirus ''Betaretrovirus'' is a genus of the ''Retroviridae'' family. It has type B or type D morphology. The type B is common for a few exogenous, vertically transmitted and endogenous viruses of mice; some primate and sheep viruses are the type D. Ex ...

''.

Associated disease

Enzootic nasal adenocarcinoma

The tumors that are induced by ENTV Env have characteristics of

adenoma An adenoma is a benign tumor of epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid, prostate, and others. Some adenom ...

s and

adenocarcinoma Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ) (AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...

due to well- differentiated epithelial appearance and a less well-differentiated appearance respectively. Symptoms of nasal adenocarcinoma are similar in both goats and sheep. They include weight loss, nasal discharge with the nasal fluid being

viscous The viscosity of a fluid is a measure of its resistance to deformation at a given rate. For liquids, it corresponds to the informal concept of "thickness": for example, syrup has a higher viscosity than water. Viscosity quantifies the inter ...

and containing pus. Tumors form in the upper

nasal cavity The nasal cavity is a large, air-filled space above and behind the nose in the middle of the face. The nasal septum divides the cavity into two cavities, also known as fossae. Each cavity is the continuation of one of the two nostrils. The nasal c ...

and have a gelatinous consistency with caudal areas being having

hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vag ...

causing a brownish-red color. Symptoms of enzootic nasal adenocarcinoma do not appear until it is too late. An ovine that grows a tumor will eventually die of suffocation.

Host interactions

Pathogenesis

Tumors form in nose and are contagious. ENTV targets the respiratory system in ovine, specifically the upper-airway

epithelial cells Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellula ...

. Oncogenesis occurs in the nasal turbinate cells A typical

oncogenic virus An oncovirus or oncogenic virus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, when the term "oncornaviruses" was used to denote their RNA virus origin. With the lett ...

will cause a mutation in a host cell, causing the transformation of host cells from a protooncogene into an

oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

. ENTV is unique among retroviruses because the envelope

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

is an oncogene. It is able to induce tumors by itself. ENTV does not have a viremic stage where the virus enters the blood which is unusual.

Immune response

There is not a humoral immune response to the ENTV capsid protein meaning there are no antibodies produced by the host in response to the virus capsid. However, recent studies have shown that there is sero-conversion in response to the envelope protein if a host is exposed to the virus after a long period of time. These antibodies have proven to be important in preventing further spread of the virus. The antibodies are more likely to respond to the ENTV

envelope An envelope is a common packaging item, usually made of thin, flat material. It is designed to contain a flat object, such as a letter or card. Traditional envelopes are made from sheets of paper cut to one of three shapes: a rhombus, a shor ...

than the

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 may ...

because the envelope is located on the exterior of the virus whereas the capsid is not. The lack of an extensive immune response may be due to the face that a large portion of the ovine genome is made up of sequences that are related to the retroviruses JSRV and ENTV.

Genome structure

ENTV has a conical structure and a similar genome structure as other retroviruses with the basic structure, 5’-U5-Gag-Pro-Pol-Env-U3-3’. ENTV has characteristics of both a B type retrovirus and a D type retrovirus. Its envelope is type B and its capsid protein is type D. This means that ENTV is classified as a chimeric type B/D retrovirus. ENTV and JSRV's amino acids are similar by over 95%. This closely links the two viruses and leads to many studies comparing and contrasting the two. The 3’ end of env and the U3 LTR region contain amino acids with the least similarity making these areas important in scientific studies. ENTV 1 and ENTV 2 differ slightly in their genome. Their main differences occur in LTR, Orf-x, several regions in Gag and env TM. It is thought that this difference in the Env TM cytoplasmic tail is important in the spreading of the virus to host species.

Gag

ENTV ''

gag A gag is usually an item or device designed to prevent speech, often as a restraint device to stop the subject from calling for help and keep its wearer silent. This is usually done by blocking the mouth, partially or completely, or attempting ...

'' encodes a chain of amino acids linked by peptide bonds, or a

polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...

that contains 613 amino acids. ''Gag'' is also responsible for encoding structural proteins including the capsid protein, the matrix shell and the nucleic acid binding protein.

Pro

''Pro'' encodes a 326 amino acid polypeptide and generally works with ''gag'' to form a gag-pro polypeptide due to ribosomal frame shifting. It encodes the viral

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...

which breaks down the viral proteins into peptides and amino acids.

Pol

'' Pol'' encodes a 870 amino acid peptide. It is usually translated to make a gag-pro-pol polypeptide due to ribosomal frame shifting. Inside the ''pol'' gene is an open reading frame, Orf-x which is abnormal for simple retroviruses. Pol is important because it encodes

reverse transcriptase A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...

and

integrase Retroviral integrase (IN) is an enzyme produced by a retrovirus (such as HIV) that integrates—forms covalent links between—its genetic information into that of the host cell it infects. Retroviral INs are not to be confused with phage int ...

Env

'' Env'' is generated by splicing and overlaps ''pol'' at the start. It encodes surface and transmembrane envelope proteins by being cleaved twice, a polypeptide precursor, and a

hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...

region. ''Env'' plays a large role in the functionality of ENTV. Env is important in ENVT tissue selectivity.

LTR

LTR is 374 bases long and contains the primer binding site and the polypurine tract. It is made up of inverted repeat sequences GCAG and CTGC. tRNALys1,2 is the reverse transcriptase primer for ENVT. The U3 region of LTR is important for replication and transcription regulatory signaling. The U3 region is also important in tissue selectivity.

Receptor and entry

The cellular receptor for ENTV is hyaluronidase 2 (Hyal2) in sheep. Hyal2 is a cell surface molecule that is anchored by

glycosylphosphatidylinositol Glycosylphosphatidylinositol (), or glycophosphatidylinositol, or GPI in short, is a phosphoglyceride that can be attached to the C-terminus of a protein during posttranslational modification. The resulting GPI-anchored proteins play key roles in ...

. ENTV's binding is very restrictive compared to other retroviruses but it is also able to bind to human and bovine Hyal2

homologs A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same locus (genetics), loci where they pr ...

. ENTV entry is pH-dependent which is a unique feature among retroviruses. An extremely low pH of 4.5 is needed for the virus to perform fusion activation and cell entry this is much lower than JSRV which requires a ph of around 6. Fusion activation of ENTV requires a lower pH than cell entry. An over expression of Hya2 is required for ENTV infection. ENTV may prefer to replicate in the nasal turbinate chondrocytes because of the high concentration of the receptor. The low pH is beneficial to the virus by creating a tumor prone environment that activates HA degradation enzymes. The TM subunit of the ''env'' gene plays an important role in the entry of ENTV into a cell. The SU subunit of the ''env'' gene also plays an important role in cell entry by influencing the low pH-dependent fusion activity.

References

{{Taxonbar, from=Q60790724 Betaretroviruses