{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T12:20:13Z","timestamp":1789215613899,"version":"build-2803163510"},"reference-count":63,"publisher":"American Society for Microbiology","issue":"15","license":[{"start":{"date-parts":[[2015,8,1]],"date-time":"2015-08-01T00:00:00Z","timestamp":1438387200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2015,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Natural killer (NK) cell-deficient patients are particularly susceptible to severe infection with herpesviruses, especially varicella-zoster virus (VZV) and herpes simplex virus 1 (HSV-1). The critical role that NK cells play in controlling these infections denotes an intricate struggle for dominance between virus and NK cell antiviral immunity; however, research in this area has remained surprisingly limited. Our study addressed this absence of knowledge and found that infection with VZV was not associated with enhanced NK cell activation, suggesting that the virus uses specific mechanisms to limit NK cell activity. Analysis of viral regulation of ligands for NKG2D, a potent activating receptor ubiquitously expressed on NK cells, revealed that VZV differentially modulates expression of the NKG2D ligands MICA, ULBP2, and ULBP3 by upregulating MICA expression while reducing ULBP2 and ULBP3 expression on the surface of infected cells. Despite being closely related to VZV, infection with HSV-1 produced a remarkably different effect on NKG2D ligand expression. A significant decrease in MICA, ULBP2, and ULBP3 was observed with HSV-1 infection at a total cellular protein level, as well as on the cell surface. We also demonstrate that HSV-1 differentially regulates expression of an additional NKG2D ligand, ULBP1, by reducing cell surface expression while total protein levels are unchanged. Our findings illustrate both a striking point of difference between two closely related alphaherpesviruses, as well as suggest a powerful capacity for VZV and HSV-1 to evade antiviral NK cell activity through novel modulation of NKG2D ligand expression.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>Patients with deficiencies in NK cell function experience an extreme susceptibility to infection with herpesviruses, in particular, VZV and HSV-1. Despite this striking correlation, research into understanding how these two alphaherpesviruses interact with NK cells is surprisingly limited. Through examination of viral regulation of ligands to the activating NK cell receptor NKG2D, we reveal patterns of modulation by VZV, which were unexpectedly varied in response to regulation by HSV-1 infection. Our study begins to unravel the undoubtedly complex interactions that occur between NK cells and alphaherpesvirus infection by providing novel insights into how VZV and HSV-1 manipulate NKG2D ligand expression to modulate NK cell activity, while also illuminating a distinct variation between two closely related alphaherpesviruses.<\/jats:p>","DOI":"10.1128\/jvi.00292-15","type":"journal-article","created":{"date-parts":[[2015,5,21]],"date-time":"2015-05-21T02:41:33Z","timestamp":1432176093000},"page":"7932-7943","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["Varicella-Zoster Virus and Herpes Simplex Virus 1 Differentially Modulate NKG2D Ligand Expression during Productive Infection"],"prefix":"10.1128","volume":"89","author":[{"given":"Tessa M.","family":"Campbell","sequence":"first","affiliation":[{"name":"Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian P.","family":"McSharry","sequence":"additional","affiliation":[{"name":"Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Steain","sequence":"additional","affiliation":[{"name":"Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry","family":"Slobedman","sequence":"additional","affiliation":[{"name":"Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allison","family":"Abendroth","sequence":"additional","affiliation":[{"name":"Discipline of Infectious Diseases and Immunology, Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1017\/CBO9780511545313.006"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/2042-4280-3-5"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.2217\/fvl.12.116"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13365-013-0189-3"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198906293202605"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V88.8.3022.bloodjournal8883022"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.1996.tb08295.x"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-2478(00)00169-3"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1286-4579(02)00038-2"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2004.11.022"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2005.06.028"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.07.020"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/375411a0"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1086\/517821"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.10.4878-4888.2001"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00711-07"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0072050"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(90)90097-S"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni1581"},{"key":"e_1_3_2_21_2","first-page":"182","article-title":"Interleukin 2 enhances natural killing of varicella-zoster virus-infected targets","volume":"65","author":"Ito M","year":"1986","unstructured":"Ito M, Bandyopadhyay S, Matsumoto-Kobayashi M, Clark SC, Miller D, Starr SE. 1986. Interleukin 2 enhances natural killing of varicella-zoster virus-infected targets. Clin Exp Immunol 65:182\u2013189.","journal-title":"Clin Exp Immunol"},{"key":"e_1_3_2_22_2","doi-asserted-by":"crossref","first-page":"4243","DOI":"10.4049\/jimmunol.136.11.4243","article-title":"Demonstration of NK cell-mediated lysis of varicella-zoster virus (VZV)-infected cells: characterization of the effector cells","volume":"136","author":"Tilden AB","year":"1986","unstructured":"Tilden AB, Cauda R, Grossi CE, Balch CM, Lakeman AD, Whitley RJ. 1986. Demonstration of NK cell-mediated lysis of varicella-zoster virus (VZV)-infected cells: characterization of the effector cells. J Immunol 136:4243\u20134248.","journal-title":"J Immunol"},{"key":"e_1_3_2_23_2","doi-asserted-by":"crossref","first-page":"2666","DOI":"10.4049\/jimmunol.134.4.2666","article-title":"Human natural killer cells limit replication of herpes simplex virus type 1 in vitro","volume":"134","author":"Fitzgerald PA","year":"1985","unstructured":"Fitzgerald PA, Mendelsohn M, Lopez C. 1985. Human natural killer cells limit replication of herpes simplex virus type 1 in vitro. J Immunol 134:2666\u20132672.","journal-title":"J Immunol"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1086\/512862"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2009.02241.x"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/359869"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5428.727"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/3-540-27743-9_6"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri2144"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00299"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-032712-095951"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.22.12445"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(01)00095-4"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2006.05.092"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1140956"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200939502"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1000789"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004058"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002362"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707883105"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2009.03.003"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.2.965-974.1998"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-2-3-357"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.75.7.3240-3249.2001"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2004.08.008"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-83-20354"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00122-08"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.9.4775"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcv.2007.10.027"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02251-07"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.178.2.961"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1348-0421.1998.tb02349.x"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/s002510100325"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2010.01.002"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2006.02.009"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2013.06.013"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01175-09"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.5.3098"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2015.01.029"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1177\/095632020101200103"},{"key":"e_1_3_2_61_2","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1177\/135965350601100805","article-title":"Antiviral activity of proteasome inhibitors in herpes simplex virus-1 infection: role of nuclear factor-kappaB","volume":"11","author":"La Frazia S","year":"2006","unstructured":"La Frazia S, Amici C, Santoro MG. 2006. Antiviral activity of proteasome inhibitors in herpes simplex virus-1 infection: role of nuclear factor-kappaB. Antivir Ther 11:995\u20131004.","journal-title":"Antivir Ther"},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2011.00085"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1000723"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1409485111"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00292-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00292-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,10]],"date-time":"2023-08-10T19:25:05Z","timestamp":1691695505000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.00292-15"}},"subtitle":[],"editor":[{"given":"L.","family":"Hutt-Fletcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,8]]},"references-count":63,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2015,8]]}},"alternative-id":["10.1128\/JVI.00292-15"],"URL":"https:\/\/doi.org\/10.1128\/jvi.00292-15","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8]]},"assertion":[{"value":"2015-04-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-05-15","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-07-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}