{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T03:22:55Z","timestamp":1789788175800,"version":"4.0.1"},"reference-count":51,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN 41625-2013"],"award-info":[{"award-number":["RGPIN 41625-2013"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Major histocompatibility complex class I (MHC-I) molecules play a critical role in the host\u2019s antiviral response by presenting virus-derived antigenic peptides to cytotoxic T lymphocytes (CTLs), enabling the clearance of virus-infected cells. Human adenoviruses evade CTL-mediated cell lysis, in part, by interfering directly with the MHC-I antigen presentation pathway through the expression of E3-19K, which binds both MHC-I and the transporter associated with antigen processing protein and sequestering MHC-I within the endoplasmic reticulum. Fowl adenoviruses have no homologues of E3-19K. Here, we show that representative virus isolates of the species Fowl aviadenovirus C, Fowl aviadenovirus D, and Fowl aviadenovirus E downregulate the cell surface expression of MHC-I in chicken hepatoma cells, resulting in 71%, 11%, and 14% of the baseline expression level, respectively, at 12 h post-infection. Furthermore, this work reports that FAdV-9 downregulates cell surface MHC-I through a minimum of two separate mechanisms\u2014a lysosomal-independent mechanism that requires the presence of the fowl adenovirus early 1 (FE1) transcription unit located within the left terminal genomic region between nts 1 and 6131 and a lysosomal-dependent mechanism that does not require the presence of FE1. These results establish a new functional role for the FE1 transcription unit in immune evasion. These studies provide important new information about the immune evasion of FAdVs and will enhance our understanding of the pathogenesis of inclusion body hepatitis and advance the progress made in next-generation FAdV-based vectors.<\/jats:p>","DOI":"10.3390\/v13112211","type":"journal-article","created":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T21:57:49Z","timestamp":1635976669000},"page":"2211","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Downregulation of Cell Surface Major Histocompatibility Complex Class I Expression Is Mediated by the Left-End Transcription Unit of Fowl Adenovirus 9"],"prefix":"10.3390","volume":"13","author":[{"given":"Bryan D.","family":"Griffin","sequence":"first","affiliation":[{"name":"Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Corredor","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanlong","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9va","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/S0167-5699(00)01699-6","article-title":"Viral mechanisms of immune evasion","volume":"21","author":"Alcami","year":"2000","journal-title":"Immunol. Today"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2939","DOI":"10.1128\/jvi.70.5.2939-2949.1996","article-title":"The complete DNA sequence and genomic organization of the avian adenovirus CELO","volume":"70","author":"Chiocca","year":"1996","journal-title":"J. Virol."},{"key":"ref_3","first-page":"1833","article-title":"The complete nucleotide sequence of fowl adenovirus type 8","volume":"81","author":"Ojkic","year":"2000","journal-title":"J. Gen. Virol."},{"key":"ref_4","unstructured":"Bamford, D.H., and Zuckerman, M. (2021). Adenoviruses (Adenoviridae). Encyclopedia of Virology, Academic Press. [4th ed.]."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Swayne, D., Glisson, J., McDougald, L., Nolan, L., Suarez, D., and Nair, V. (2013). Aviadenovirus Infections. Diseases of Poultry, John Wiley and Sons. [13th ed.].","DOI":"10.1002\/9781119421481.ch9"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/j.vetmic.2016.02.008","article-title":"Detailed molecular analyses of the hexon loop-1 and fibers of fowl aviadenoviruses reveal new insights into the antigenic relationship and confirm that specific genotypes are involved in field outbreaks of inclusion body hepatitis","volume":"186","author":"Schachner","year":"2016","journal-title":"Vet. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1080\/03079457.2017.1385724","article-title":"Fowl adenovirus-induced diseases and strategies for their control\u2014A review on the current global situation","volume":"47","author":"Schachner","year":"2018","journal-title":"Avian. Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1006\/viro.2002.1583","article-title":"Unique features of fowl adenovirus 9 gene transcription","volume":"302","author":"Ojkic","year":"2002","journal-title":"Virology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1099\/vir.0.19497-0","article-title":"Genetic content and evolution of adenoviruses","volume":"84","author":"Davison","year":"2003","journal-title":"J. Gen. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1099\/vir.0.013839-0","article-title":"A region at the left end of the fowl adenovirus 9 genome that is non-essential in vitro has consequences in vivo","volume":"91","author":"Corredor","year":"2010","journal-title":"J. Gen. Virol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1128\/CVI.00187-13","article-title":"Oral inoculation of chickens with a candidate fowl adenovirus 9 vector","volume":"20","author":"Deng","year":"2013","journal-title":"Clin. Vaccine Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.virol.2016.07.023","article-title":"Characterization and functional studies of fowl adenovirus 9 dUTPase","volume":"497","author":"Deng","year":"2016","journal-title":"Virology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1089\/vim.2017.0068","article-title":"Fowl Aviadenovirus 9 dUTPase Plays a Role in Regulation of the Host Immune Response","volume":"30","author":"Deng","year":"2017","journal-title":"Viral Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1038\/nri2575","article-title":"MHC class I antigen presentation: Learning from viral evasion strategies","volume":"9","author":"Hansen","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/j.1365-2567.2008.02804.x","article-title":"Pathogen evasion strategies for the major histocompatibility complex class I assembly pathway","volume":"124","author":"Antoniou","year":"2008","journal-title":"Immunology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1128\/jvi.61.3.787-795.1987","article-title":"Adenovirus early region 1A modulation of interferon antiviral activity","volume":"61","author":"Anderson","year":"1987","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/0042-6822(88)90689-7","article-title":"Adenovirus type 12 E1A gene represses accumulation of MHC class I mRNAs at the level of transcription","volume":"165","author":"Friedman","year":"1988","journal-title":"Virology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1016\/S0092-8674(85)80079-9","article-title":"An adenovirus type 2 glycoprotein blocks cell surface expression of human histocompatibility class I antigens","volume":"41","author":"Burgert","year":"1985","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1084\/jem.174.6.1629","article-title":"Retention of adenovirus E19 glycoprotein in the endoplasmic reticulum is essential to its ability to block antigen presentation","volume":"174","author":"Cox","year":"1991","journal-title":"J. Exp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/BF02970147","article-title":"Lessons in detente or know thy host: The immunomodulatory gene products of myxoma virus","volume":"28","author":"Zuniga","year":"2003","journal-title":"J. Biosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/S0166-0934(98)00062-7","article-title":"Growth characteristics of fowl adenovirus type 8 in a chicken hepatoma cell line","volume":"74","author":"Alexander","year":"1998","journal-title":"J. Virol. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1089\/vim.2006.19.167","article-title":"Marek\u2019s disease virus-induced transient paralysis is associated with cytokine gene expression in the nervous system","volume":"19","author":"Hunter","year":"2006","journal-title":"Viral Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.virol.2007.09.013","article-title":"Host responses are induced in feathers of chickens infected with Marek\u2019s disease virus","volume":"370","author":"Hunter","year":"2008","journal-title":"Virology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","article-title":"A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding","volume":"72","author":"Bradford","year":"1976","journal-title":"Anal. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/0022-1759(87)90175-X","article-title":"A simple method to eliminate the antigenicity of surface class I MHC molecules from the membrane of viable cells by acid treatment at pH 3","volume":"100","author":"Sugawara","year":"1987","journal-title":"J. Immunol. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9034","DOI":"10.1128\/JVI.00711-07","article-title":"Downregulation of class I major histocompatibility complex surface expression by varicella-zoster virus involves open reading frame 66 protein kinase-dependent and -independent mechanisms","volume":"81","author":"Eisfeld","year":"2007","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1128\/JVI.78.3.1109-1120.2004","article-title":"Downregulation of Major Histocompatibility Complex Class I by Human Ubiquitin Ligases Related to Viral Immune Evasion Proteins","volume":"78","author":"Bartee","year":"2004","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1073\/pnas.94.5.1896","article-title":"Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome","volume":"94","author":"Hughes","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Washietl, S., and Eisenhaber, F. (2003). Reannotation of the CELO genome characterizes a set of previously unassigned open reading frames and points to novel modes of host interaction in avian adenoviruses. BMC Bioinform., 4.","DOI":"10.1186\/1471-2105-4-55"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2019","DOI":"10.1099\/vir.0.80879-0","article-title":"Deletion of open reading frames 9, 10 and 11 from the avian adenovirus CELO genome: Effect on biodistribution and humoral responses","volume":"86","author":"Jestin","year":"2005","journal-title":"J. Gen. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s11262-005-0031-y","article-title":"Sequence analysis of the left end of fowl adenovirus genomes","volume":"33","author":"Corredor","year":"2006","journal-title":"Virus Genes"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1099\/vir.0.030064-0","article-title":"Coding potential and transcript analysis of fowl adenovirus 4: Insight into upstream ORFs as common sequence features in adenoviral transcripts","volume":"92","author":"Griffin","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/sj.onc.1205008","article-title":"Down-regulation of MHC class I by bovine papillomavirus E5 oncoproteins","volume":"21","author":"Ashrafi","year":"2002","journal-title":"Oncogene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1126\/science.3014660","article-title":"The E5 transforming gene of bovine papillomavirus encodes a small, hydrophobic polypeptide","volume":"233","author":"Schlegel","year":"1986","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"325","DOI":"10.4049\/jimmunol.168.1.325","article-title":"IFN-alpha secretion by type 2 predendritic cells up-regulates MHC class I in the HIV-1-infected thymus","volume":"168","author":"Keir","year":"2002","journal-title":"J. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1002\/j.1460-2075.1991.tb08017.x","article-title":"Activation of the platelet-derived growth factor receptor by the bovine papillomavirus E5 transforming protein","volume":"10","author":"Petti","year":"1991","journal-title":"EMBO J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"7808","DOI":"10.1038\/sj.onc.1205885","article-title":"The bovine papillomavirus oncoprotein E5 retains MHC class I molecules in the Golgi apparatus and prevents their transport to the cell surface","volume":"21","author":"Marchetti","year":"2002","journal-title":"Oncogene"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Schaefer, M.R., Wonderlich, E.R., Roeth, J.F., Leonard, J.A., and Collins, K.L. (2008). HIV-1 Nef targets MHC-I and CD4 for degradation via a final common beta-COP-dependent pathway in T cells. PLoS Pathog., 4.","DOI":"10.1371\/journal.ppat.1000131"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"12347","DOI":"10.1128\/JVI.75.24.12347-12358.2001","article-title":"A human herpesvirus 7 glycoprotein, U21, diverts major histocompatibility complex class I molecules to lysosomes","volume":"75","author":"Hudson","year":"2001","journal-title":"J. Virol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5522","DOI":"10.1128\/JVI.76.11.5522-5531.2002","article-title":"Kaposi\u2019s Sarcoma-Associated Herpesvirus K3 Utilizes the Ubiquitin-Proteasome System in Routing Class I Major Histocompatibility Complexes to Late Endocytic Compartments","volume":"76","author":"Lorenzo","year":"2002","journal-title":"J. Virol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jviromet.2015.07.017","article-title":"Rapid generation of fowl adenovirus 9 vectors","volume":"223","author":"Pei","year":"2015","journal-title":"J. Virol. Methods"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.virusres.2018.12.001","article-title":"Fowl adenovirus 9 ORF19, a lipase homolog, is nonessential for virus replication and is suitable for foreign gene expression","volume":"260","author":"Pei","year":"2019","journal-title":"Virus Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1038\/cmi.2014.105","article-title":"Classical and non-classical MHC I molecule manipulation by human cytomegalovirus: So many targets-but how many arrows in the quiver?","volume":"12","author":"Halenius","year":"2015","journal-title":"Cell. Mol. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6517","DOI":"10.1128\/JVI.73.8.6517-6525.1999","article-title":"Characterization of CELO virus proteins that modulate the pRb\/E2F pathway","volume":"73","author":"Lehrmann","year":"1999","journal-title":"J. Virol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sharp, T.M., Guix, S., Katayama, K., Crawford, S.E., and Estes, M.K. (2010). Inhibition of cellular protein secretion by norwalk virus nonstructural protein p22 requires a mimic of an endoplasmic reticulum export signal. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0013130"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6465","DOI":"10.1093\/emboj\/19.23.6465","article-title":"Immobilization of the early secretory pathway by a virus glycoprotein that binds to microtubules","volume":"19","author":"Xu","year":"2000","journal-title":"EMBO J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1128\/JVI.00393-06","article-title":"Inhibition of the secretory pathway by foot-and-mouth disease virus 2BC protein is reproduced by coexpression of 2B with 2C, and the site of inhibition is determined by the subcellular location of 2C","volume":"81","author":"Moffat","year":"2007","journal-title":"J. Virol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6785","DOI":"10.1128\/JVI.00198-07","article-title":"Coxsackievirus B3 Proteins Directionally Complement Each Other To Downregulate Surface Major Histocompatibility Complex Class I","volume":"81","author":"Cornell","year":"2007","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"11671","DOI":"10.1128\/JVI.01170-14","article-title":"Human Rhinovirus 16 Causes Golgi Apparatus Fragmentation without Blocking Protein Secretion","volume":"88","author":"Mousnier","year":"2014","journal-title":"J. Virol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"13790","DOI":"10.1073\/pnas.250483097","article-title":"MHC I-dependent antigen presentation is inhibited by poliovirus protein 3A","volume":"97","author":"Deitz","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/11\/2211\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:25:15Z","timestamp":1760167515000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/11\/2211"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,3]]},"references-count":51,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["v13112211"],"URL":"https:\/\/doi.org\/10.3390\/v13112211","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,3]]}}}