{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T21:09:54Z","timestamp":1785532194812,"version":"3.56.0"},"reference-count":70,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"crossref","award":["20H5692"],"award-info":[{"award-number":["20H5692"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology of Japan","doi-asserted-by":"crossref","award":["22H04803"],"award-info":[{"award-number":["22H04803"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology of Japan","doi-asserted-by":"crossref","award":["22H05584"],"award-info":[{"award-number":["22H05584"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100002241","name":"Japan Science and Technology Agency","doi-asserted-by":"crossref","award":["JPMJPR22R5"],"award-info":[{"award-number":["JPMJPR22R5"]}],"id":[{"id":"10.13039\/501100002241","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP23wm0225035, JP22fk0108640, JP223fa627001, JP20wm0125002, JP23wm0225031"],"award-info":[{"award-number":["JP23wm0225035, JP22fk0108640, JP223fa627001, JP20wm0125002, JP23wm0225031"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"crossref","award":["JP22gm1610008"],"award-info":[{"award-number":["JP22gm1610008"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007451","name":"Cell Science Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100007451","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2024,7,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>Although the herpes simplex virus type 1 (HSV-1) genome was thought to contain approximately 80 different protein coding sequences (CDSs), recent multi-omics analyses reported HSV-1 encodes more than 200 potential CDSs. However, few of the newly identified CDSs were confirmed to be expressed at the peptide or protein level in HSV-1-infected cells. Furthermore, the impact of the proteins they encode on HSV-1 infection is largely unknown. This study focused on a newly identified CDS, UL31.6. Re-analyzation of our previous chemical proteomics data verified that UL31.6 was expressed at the peptide level in HSV-1-infected cells. Antisera raised against a viral protein encoded by UL31.6 (pUL31.6) reacted with a protein with an approximate molecular mass of 37 \u2009kDa in lysates of Vero cells infected with each of three HSV-1 strains. pUL31.6 was efficiently dissociated from virions in high-salt solution. A UL31.6-null mutation had a minimal effect on HSV-1 gene expression, replication, cell-to-cell spread, and morphogenesis in Vero cells; in contrast, it significantly reduced HSV-1 cell-to-cell spread in three neural cells but not in four non-neural cells including Vero cells. The UL31.6-null mutation also significantly reduced the mortality and viral replication in the brains of mice after intracranial infection, but had minimal effects on pathogenic manifestations in and around the eyes, and viral replication detected in the tear films of mice after ocular infection. These results indicated that pUL31.6 was a tegument protein and specifically acted as a neurovirulence factor by potentially promoting viral transmission between neuronal cells in the central nervous system.<\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>Recent multi-omics analyses reported the herpes simplex virus type 1 (HSV-1) genome encodes an additional number of potential coding sequences (CDSs). However, the expressions of these CDSs at the peptide or protein levels and the biological effects of these CDSs on HSV-1 infection remain largely unknown. This study annotated a cryptic orphan CDS, termed UL31.6, an HSV-1 gene that encodes a tegument protein with an approximate molecular mass of 37 \u2009kDa, which specifically acts as a neurovirulence factor. Our study indicates that HSV-1 proteins important for viral pathogenesis remain to be identified and a comprehensive understanding of the pathogenesis of HSV-1 will require not only the identification of cryptic orphan CDSs using emerging technologies but also step-by-step and in-depth analyses of each of the cryptic orphan CDSs.<\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/jvi.00747-24","type":"journal-article","created":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T13:04:34Z","timestamp":1717160674000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Identification of a novel neurovirulence factor encoded by the cryptic orphan gene UL31.6 of herpes simplex virus 1"],"prefix":"10.1128","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-3815-5371","authenticated-orcid":false,"given":"Akihisa","family":"Kato","sequence":"first","affiliation":[{"name":"Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"Research Center for Asian Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"PRESTO, Japan Science and Technology Agency (JST), Kawaguchi, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryoji","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kousuke","family":"Takeshima","sequence":"additional","affiliation":[{"name":"Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhei","family":"Maruzuru","sequence":"additional","affiliation":[{"name":"Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoto","family":"Koyanagi","sequence":"additional","affiliation":[{"name":"Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tohru","family":"Natsume","sequence":"additional","affiliation":[{"name":"Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Kusano","sequence":"additional","affiliation":[{"name":"Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan"},{"name":"Department of Proteomics, National Cancer Center Research institute, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shungo","family":"Adachi","sequence":"additional","affiliation":[{"name":"Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST), Tokyo, Japan"},{"name":"Department of Proteomics, National Cancer Center Research institute, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuichi","family":"Kawano","sequence":"additional","affiliation":[{"name":"Faculty of Mathematics, Kyushu University, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8232-6925","authenticated-orcid":true,"given":"Yasushi","family":"Kawaguchi","sequence":"additional","affiliation":[{"name":"Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"Research Center for Asian Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan"},{"name":"The University of Tokyo, Pandemic Preparedness, Infection and Advanced Research Center, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","first-page":"235","volume-title":"Fields Virology","author":"Howley PM","year":"2022","unstructured":"Howley PM, Knipe DM. 2022. Herpes simplex viruses: mechanisms of lytic and latent infection, p 235\u2013296. In Knipe DMHeldwein EF, Mohr IJ, Sodroski CN (ed), Fields Virology, 7th ed. Lippincott-Williams &Wilkins, Philadelphia, PA.","edition":"7"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1090284"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00904-08"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-010-0120-0"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6980"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/v13122395"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.10.002"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.108815"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0262"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.01.021"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-00806-2"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15992-5"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-08734-9"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-18718-9"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.68.7.4251-4261.1994"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.3.2463-2473.1998"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(73)90398-x"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1999.0090"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00633-13"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.76.17.8939-8952.2002"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.9.7108-7114.1998"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00126-10"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2005.00379.x"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00127-17"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00128-12"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02799-14"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02196-16"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03707-13"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.53789"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01035-18"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00900-20"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(07)70267-3"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.000128"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-021-00417-w"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abo4435"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02681-07"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01413-20"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92931"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.01429-22"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-2-3-357"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt0997-871"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1068539"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.2144\/000112096"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00044-08"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.77.2.1382-1391.2003"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-018-0203-2"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2017.12.014"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.77.4.2359-2368.2003"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.14.9325-9331.2005"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01634-14"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02710-13"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01258-16"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00845-11"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01055-20"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.73.5.4456-4460.1999"},{"key":"e_1_3_4_57_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.71.10.7328-7336.1997"},{"key":"e_1_3_4_58_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02376-15"},{"key":"e_1_3_4_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01704-21"},{"key":"e_1_3_4_60_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.03300-13"},{"key":"e_1_3_4_61_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01447-09"},{"key":"e_1_3_4_62_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.187.3.341"},{"key":"e_1_3_4_63_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2014.03.004"},{"key":"e_1_3_4_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2014.01.009"},{"key":"e_1_3_4_65_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41417-019-0091-0"},{"key":"e_1_3_4_66_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1348-0421.2008.00104.x"},{"key":"e_1_3_4_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(88)90417-5"},{"key":"e_1_3_4_68_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3033824"},{"key":"e_1_3_4_69_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.11.5069-5075.2001"},{"key":"e_1_3_4_70_2","doi-asserted-by":"publisher","DOI":"10.1128\/mSphere.00073-19"},{"key":"e_1_3_4_71_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.673763"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/jvi.00747-24","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/jvi.00747-24","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T13:19:37Z","timestamp":1721740777000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/jvi.00747-24"}},"subtitle":[],"editor":[{"given":"Anna Ruth","family":"Cliffe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,7,23]]},"references-count":70,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,7,23]]}},"alternative-id":["10.1128\/jvi.00747-24"],"URL":"https:\/\/doi.org\/10.1128\/jvi.00747-24","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,23]]},"assertion":[{"value":"2024-05-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-03","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-31","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e00747-24"}}