Enzootic nasal tumor virus

The enzootic nasal tumor virus of the betaretrovirus genus is a carcinogenic retrovirus that causes enzootic nasal adenocarcinoma in sheep and goats.[1] Strain ENTV-1 is found in sheep and strain ENTV-2 is found in goats.[2][3] The virus causes tumor growth in the upper nasal cavity and is closely related to JSRV which also causes respiratory tumors in ovine.[4] The disease, enzootic nasal adenocarcinoma is common in North America and is found in sheep and goats on every continent except New Zealand and Australia.[5] There are more than 27 betaretroviruses similar to ENVT and JSRV in the ovine genome.[6][7] In the future, research on ENTV may become important in studying viruses that cause human lung cancer.[8]

Enzootic nasal tumor virus
Ewe infected with enzootic nasal tumor virus.
Virus classification
Group:
Group VI (ssRNA-RT)
Order:
Ortervirales
Family:
Retroviridae
Subfamily:
Orthoretrovirinae
Genus:
Betaretrovirus
Species:
Enzootic nasal tumor virus

Classification

ENTV belongs to the family Retroviridae, to the subfamily Orthoretrovirinae and the genus Betaretrovirus.

Associated disease

Enzootic nasal adenocarcinoma

The tumors that are induced by ENTV Env have characteristics of adenomas and adenocarcinoma due to well-differentiated epithelial appearance and a less well-differentiated appearance respectively.[9] Symptoms of nasal adenocarcinoma are similar in both goats and sheep. They include weight loss, nasal discharge with the nasal fluid being viscous and containing pus. Tumors form in the upper nasal cavity and have a gelatinous consistency with caudal areas being having hemorrhage causing a brownish-red color.[4] Symptoms of enzootic nasal adenocarcinoma do not appear until it is too late. An ovine that grows a tumor will eventually die of suffocation.[6]

Host interactions

Pathogenesis

Tumors form in nose and are contagious. ENTV targets the respiratory system in ovine, specifically the upper-airway epithelial cells.[6] Oncogenesis occurs in the nasal turbinate cells [8] A typical oncogenic virus will cause a mutation in a host cell, causing the transformation of host cells from a protooncogene into an oncogene. ENTV is unique among retroviruses because the envelope glycoprotein is an oncogene. It is able to induce tumors by itself.[10]  ENTV does not have a viremic stage where the virus enters the blood which is unusual.[11]

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.[12] 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 than the capsid because the envelope is located on the exterior of the virus whereas the capsid is not.[13] 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.[2] 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.[4]

Gag

ENTV gag encodes a chain of amino acids linked by peptide bonds, or a polypeptide 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.[2]

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 which breaks down the viral proteins into peptides and amino acids.[2]

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 and integrase.[2]

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 region. Env plays a large role in the functionality of ENTV.[2] Env is important in ENVT tissue selectivity.[7]

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.[2] The U3 region of LTR is important for replication and transcription regulatory signaling.[4] The U3 region is also important in tissue selectivity.[7]

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.  ENTV's binding is very restrictive compared to other retroviruses but it is also able to bind to human and bovine Hyal2 homologs.[8] 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.[14] 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.[7] The low pH is beneficial to the virus by creating a tumor prone environment that activates HA degradation enzymes.[15] The TM subunit of the env gene plays an important role in the entry of ENTV into a cell.[2]  The SU subunit of the env gene also plays an important role in cell entry by influencing the low pH-dependent fusion activity.[14]

See also

References
  1. Yu DL, Linnerth-Petrik NM, Halbert CL, Walsh SR, Miller AD, Wootton SK (August 2011). "Jaagsiekte sheep retrovirus and enzootic nasal tumor virus promoters drive gene expression in all airway epithelial cells of mice but only induce tumors in the alveolar region of the lungs". Journal of Virology. 85 (15): 7535–45. doi:10.1128/JVI.00400-11. PMC 3147915. PMID 21593165.
  2. Cousens C, Minguijon E, Dalziel RG, Ortin A, Garcia M, Park J, Gonzalez L, Sharp JM, de las Heras M. Complete Sequence of Enzootic Nasal Tumor Virus, a Retrovirus Associated with Transmissible Intranasal Tumors of Sheep. American Society for Microbiology. OCLC 679408708.
  3. Ortín A, Cousens C, Minguijón E, Pascual Z, Villarreal MP, Sharp JM, Heras M (August 2003). "Characterization of enzootic nasal tumour virus of goats: complete sequence and tissue distribution". The Journal of General Virology. 84 (Pt 8): 2245–52. doi:10.1099/vir.0.19125-0. PMID 12867657.
  4. He Y, Zhang Q, Wang J, Zhou M, Fu M, Xu X (July 2017). "Full-length genome sequence analysis of enzootic nasal tumor virus isolated from goats in China". Virology Journal. 14 (1): 141. doi:10.1186/s12985-017-0795-4. PMC 5530571. PMID 28747230.
  5. Walsh SR, Linnerth-Petrik NM, Laporte AN, Menzies PI, Foster RA, Wootton SK (July 2010). "Full-length genome sequence analysis of enzootic nasal tumor virus reveals an unusually high degree of genetic stability". Virus Research. 151 (1): 74–87. doi:10.1016/j.virusres.2010.04.002. PMID 20398709.
  6. De las Heras M, Ortín A, Cousens C, Minguijón E, Sharp JM (2003). "Enzootic nasal adenocarcinoma of sheep and goats". Current Topics in Microbiology and Immunology. Springer Berlin Heidelberg. 275: 201–23. doi:10.1007/978-3-642-55638-8_8. ISBN 978-3-642-62897-9. PMID 12596900.
  7. Rosales Gerpe MC, van Lieshout LP, Domm JM, Ingrao JC, Datu J, Walsh SR, et al. (November 2019). "The U3 and Env Proteins of Jaagsiekte Sheep Retrovirus and Enzootic Nasal Tumor Virus Both Contribute to Tissue Tropism". Viruses. 11 (11): 1061. doi:10.3390/v11111061. PMID 31739606.
  8. Dirks C, Duh FM, Rai SK, Lerman MI, Miller AD (March 2002). "Mechanism of cell entry and transformation by enzootic nasal tumor virus". Journal of Virology. 76 (5): 2141–9. doi:10.1128/jvi.76.5.2141-2149.2002. PMID 11836391.
  9. Wootton SK, Halbert CL, Miller AD (September 2006). "Envelope proteins of Jaagsiekte sheep retrovirus and enzootic nasal tumor virus induce similar bronchioalveolar tumors in lungs of mice". Journal of Virology. 80 (18): 9322–5. doi:10.1128/JVI.00865-06. PMC 1563922. PMID 16940543.
  10. Caporale M, Cousens C, Centorame P, Pinoni C, De las Heras M, Palmarini M (August 2006). "Expression of the jaagsiekte sheep retrovirus envelope glycoprotein is sufficient to induce lung tumors in sheep". Journal of Virology. 80 (16): 8030–7. doi:10.1128/JVI.00474-06. PMC 1563803. PMID 16873259.
  11. Walsh SR, Stinson KJ, Menzies PI, Wootton SK (August 2014). "Development of an ante-mortem diagnostic test for enzootic nasal tumor virus and detection of neutralizing antibodies in host serum". The Journal of General Virology. 95 (Pt 8): 1843–54. doi:10.1099/vir.0.064956-0. PMID 24836673.
  12. Ortín A, Minguijón E, Dewar P, García M, Ferrer LM, Palmarini M, et al. (February 1998). "Lack of a specific immune response against a recombinant capsid protein of Jaagsiekte sheep retrovirus in sheep and goats naturally affected by enzootic nasal tumour or sheep pulmonary adenomatosis". Veterinary Immunology and Immunopathology. 61 (2–4): 229–37. doi:10.1016/s0165-2427(97)00149-9. PMID 9613437.
  13. Walsh SR, Stinson KJ, Wootton SK (January 2016). "Seroconversion of sheep experimentally infected with enzootic nasal tumor virus". BMC Research Notes. 9 (1): 15. doi:10.1186/s13104-015-1824-2. PMC 4704252. PMID 26744306.
  14. Côté M, Kucharski TJ, Liu SL (September 2008). "Enzootic nasal tumor virus envelope requires a very acidic pH for fusion activation and infection". Journal of Virology. 82 (18): 9023–34. doi:10.1128/JVI.00648-08. PMID 18632865.
  15. Bourguignon LY, Singleton PA, Diedrich F, Stern R, Gilad E (June 2004). "CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion". The Journal of Biological Chemistry. 279 (26): 26991–7007. doi:10.1074/jbc.m311838200. PMID 15090545.
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