{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:30:07Z","timestamp":1791412207041,"version":"4.3.3"},"reference-count":51,"publisher":"American Society for Microbiology","issue":"13","license":[{"start":{"date-parts":[[2015,7,1]],"date-time":"2015-07-01T00:00:00Z","timestamp":1435708800000},"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":[[2015,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Most blinding ocular herpetic disease is due to reactivation of herpes simplex virus 1 (HSV-1) from latency rather than to primary acute infection. No herpes simplex vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular herpes to assess the efficacy of a therapeutic vaccine based on HSV-1 gD epitopes that are recognized mainly by CD8\n            <jats:sup>+<\/jats:sup>\n            T cells from \u201cnaturally\u201d protected HLA-A*02:01-positive, HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease). Three ASYMP CD8\n            <jats:sup>+<\/jats:sup>\n            T-cell epitopes (gD\n            <jats:sub>53\u201361<\/jats:sub>\n            , gD\n            <jats:sub>70\u201378<\/jats:sub>\n            , and gD\n            <jats:sub>278\u2013286<\/jats:sub>\n            ) were linked with a promiscuous CD4\n            <jats:sup>+<\/jats:sup>\n            T-cell epitope (gD\n            <jats:sub>287\u2013317<\/jats:sub>\n            ) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an N\n            <jats:sup>\u03b5<\/jats:sup>\n            -palmitoyl-lysine moiety, a Toll-like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide vaccines. Latently infected HLA Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide vaccines, delivered as eye drops in sterile phosphate-buffered saline (PBS). The ASYMP therapeutic vaccination (i) induced HSV-specific CD8\n            <jats:sup>+<\/jats:sup>\n            T cells that prevent HSV-1 reactivation\n            <jats:italic>ex vivo<\/jats:italic>\n            from latently infected explanted trigeminal ganglia (TG), (ii) significantly reduced HSV-1 shedding detected in tears, (iii) boosted the number and function of HSV-1 gD epitope-specific CD8\n            <jats:sup>+<\/jats:sup>\n            T cells in draining lymph nodes (DLN), conjunctiva, and TG, and (iv) was associated with fewer exhausted HSV-1 gD-specific PD-1\n            <jats:sup>+<\/jats:sup>\n            TIM-3\n            <jats:sup>+<\/jats:sup>\n            CD8\n            <jats:sup>+<\/jats:sup>\n            T cells. The results underscore the potential of an ASYMP CD8\n            <jats:sup>+<\/jats:sup>\n            T-cell epitope-based therapeutic vaccine strategy against recurrent ocular herpes.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            Seventy percent to 90% of adults harbor herpes simplex virus 1 (HSV-1), which establishes lifelong latency in sensory neurons of the trigeminal ganglia. This latent state sporadically switches to spontaneous reactivation, resulting in viral shedding in tears. Most blinding herpetic disease in humans is due to reactivation of HSV-1 from latency rather than to primary acute infection. To date, there is no licensed therapeutic vaccine that can effectively stop or reduce HSV-1 reactivation from latently infected sensory ganglia and the subsequent shedding in tears. In the present study, we demonstrated that topical ocular therapeutic vaccination of latently infected HLA transgenic rabbits with a lipopeptide vaccine that contains exclusively human \u201casymptomatic\u201d CD8\n            <jats:sup>+<\/jats:sup>\n            T-cell epitopes successfully decreased spontaneous HSV-1 reactivation, as judged by a significant reduction in spontaneous shedding in tears. The findings should guide the clinical development of a safe and effective T-cell-based therapeutic herpes vaccine.\n          <\/jats:p>","DOI":"10.1128\/jvi.00788-15","type":"journal-article","created":{"date-parts":[[2015,4,16]],"date-time":"2015-04-16T02:51:56Z","timestamp":1429152716000},"page":"6619-6632","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":33,"title":["Therapeutic Immunization with a Mixture of Herpes Simplex Virus 1 Glycoprotein D-Derived \u201cAsymptomatic\u201d Human CD8\n            <sup>+<\/sup>\n            T-Cell Epitopes Decreases Spontaneous Ocular Shedding in Latently Infected HLA Transgenic Rabbits: Association with Low Frequency of Local PD-1\n            <sup>+<\/sup>\n            TIM-3\n            <sup>+<\/sup>\n            CD8\n            <sup>+<\/sup>\n            Exhausted T Cells"],"prefix":"10.1128","volume":"89","author":[{"given":"Arif A.","family":"Khan","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchi","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aziz A.","family":"Chentoufi","sequence":"additional","affiliation":[{"name":"Pathology and Clinical Laboratory Medicine, Department of Immunology, King Fahad Medical City, Riyadh, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Geertsema","sequence":"additional","affiliation":[{"name":"University Laboratory Animal Resources, University of California Irvine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nhi Thi Uyen","family":"Thai","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gargi","family":"Dasgupta","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson","family":"Osorio","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina","family":"Kalantari","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony B.","family":"Nesburn","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8509-5229","authenticated-orcid":false,"given":"Steven L.","family":"Wechsler","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, California, USA"},{"name":"Virology Research, Gavin Herbert Eye Institute and Department of Ophthalmology, University of California Irvine School of Medicine, Irvine, California, USA"},{"name":"Department of Microbiology and Molecular Genetics, University of California Irvine School of Medicine, Irvine, California, USA"},{"name":"Center for Virus Research, University of California Irvine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lbachir","family":"BenMohamed","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, University of California Irvine School of Medicine, Irvine, California, USA"},{"name":"Department of Molecular Biology &amp; Biochemistry, University of California Irvine School of Medicine, Irvine, California, USA"},{"name":"Institute for Immunology, University of California Irvine School of Medicine, Irvine, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2014.10.002"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2014.04.016"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1301415"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.1.426"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201121"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00587-11"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1006\/viro.1998.9454"},{"key":"e_1_3_2_9_2","first-page":"1163","article-title":"A therapeutic vaccine that reduces recurrent herpes simplex virus type 1 corneal disease","volume":"39","author":"Nesburn AB","year":"1998","unstructured":"Nesburn AB, Burke RL, Ghiasi H, Slanina SM, Wechsler SL. 1998. A therapeutic vaccine that reduces recurrent herpes simplex virus type 1 corneal disease. Invest Ophthalmol Vis Sci 39:1163\u20131170.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0902322"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199807303390503"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164164"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellimm.2007.01.001"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1200063"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.022301899"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1103151"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa011915"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2014.10.002"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.177.11.8037"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.10.7715-7721.1998"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2004.08.019"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/612316"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-9-221"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00692-08"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2008.81"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(02)00318-3"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.10-6522"},{"key":"e_1_3_2_28_2","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.4049\/jimmunol.1402606","article-title":"HLA-A02:01-restricted epitopes identified from the herpes simplex virus tegument protein VP11\/12 preferentially recall polyfunctional effector memory CD8+ T cells from seropositive asymptomatic individuals and protect humanized HLA-A*02:01 transgenic mice against ocular herpes","volume":"194","author":"Srivastava R","year":"2015","unstructured":"Srivastava R, Khan AA, Spencer D, Vahed H, Lopes PP, Thai NT, Wang C, Pham TT, Huang J, Scarfone VM, Nesburn AB, Wechsler SL, BenMohamed L. 2015. HLA-A02:01-restricted epitopes identified from the herpes simplex virus tegument protein VP11\/12 preferentially recall polyfunctional effector memory CD8+ T cells from seropositive asymptomatic individuals and protect humanized HLA-A*02:01 transgenic mice against ocular herpes. J Immunol 194:2232\u20132248.","journal-title":"J Immunol"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2014.01.052"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2014.02.006"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200208)32:8<2274::AID-IMMU2274>3.0.CO;2-C"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200425166"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.24.15289-15301.2005"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1542-0124(12)70164-7"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.08-2957"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1086\/505359"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1186\/1743-422X-2-67"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0610847104"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2007.00088.x"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1136\/bjo.84.4.408"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.12.6435"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2011.06.083"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.09.101"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1586\/erv.09.60"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401285"},{"key":"e_1_3_2_46_2","first-page":"945","article-title":"Reactivation of murine latent HSV infection by epinephrine iontophoresis","volume":"25","author":"Willey DE","year":"1984","unstructured":"Willey DE, Trousdale MD, Nesburn AB. 1984. Reactivation of murine latent HSV infection by epinephrine iontophoresis. Invest Ophthalmol Vis Sci 25:945\u2013950.","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00243-07"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00294-07"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0039757"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100643"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009731107"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100637"}],"container-title":["Journal of Virology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00788-15","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/JVI.00788-15","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,4]],"date-time":"2022-03-04T21:50:27Z","timestamp":1646430627000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/JVI.00788-15"}},"subtitle":[],"editor":[{"given":"L.","family":"Hutt-Fletcher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2015,7]]},"references-count":51,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2015,7]]}},"alternative-id":["10.1128\/JVI.00788-15"],"URL":"https:\/\/doi.org\/10.1128\/jvi.00788-15","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,7]]},"assertion":[{"value":"2015-03-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-04-04","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2015-06-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}