{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T14:14:17Z","timestamp":1781360057555,"version":"3.54.1"},"reference-count":48,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2018,8,7]],"date-time":"2018-08-07T00:00:00Z","timestamp":1533600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T00:00:00Z","timestamp":1536105600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Harvard University David Rockefeller Center for Latin American Studies"},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["P20GM103516"],"award-info":[{"award-number":["P20GM103516"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI110769"],"award-info":[{"award-number":["R01AI110769"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2018,9,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The 2015\u20132016 Zika virus (ZIKV) epidemic in the Americas and the Caribbean demonstrated that clinical assays to detect, distinguish, and characterize immune responses to flaviviral infections are needed. ZIKV and dengue virus (DENV) are mosquito-transmitted flaviviruses sharing overlapping geographic distributions and have significant sequence similarities that can increase the potential for antibody and T cell cross-reaction. Using nonstructural protein 1-based enzyme-linked immunosorbent assays (ELISAs), we determined the serostatus of individuals living in a region of DENV and ZIKV endemicity in Brazil, identifying individuals with primary DENV (pDENV) and primary ZIKV (pZIKV), ZIKV with primary DENV (ZIKVwpDENV), and secondary DENV (sDENV) infections; the presence of pDENV and pZIKV was further confirmed by neutralization tests. Development of an enzyme-linked immunosorbent spot (ELISPOT) assay for DENV and ZIKV structural and nonstructural (NS) protein antigens enabled us to distinguish infections by these viruses based on T cell responses and to characterize those responses. We found that gamma interferon (IFN-\u03b3) and tumor necrosis factor alpha (TNF-\u03b1) T cell responses to NS3 differentiated DENV and ZIKV infections with 94% sensitivity and 92% specificity. In general, we also showed that pDENV and sDENV cases and pZIKV and ZIKVwpDENV cases elicit similar T cell response patterns and that HIV-infected individuals show T cell responses that are lower than those shown by HIV-negative individuals. These results have important implications for DENV and ZIKV diagnostic and vaccine development and provide critical insights into the T cell response in individuals with multiple flaviviral infections.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    The potential for antibody and T cell cross-reactions to DENV and ZIKV, flaviviruses that cocirculate and can sequentially infect individuals, has complicated diagnostic and vaccine development. Our serological data show that antibodies to nonstructural protein 1 can distinguish sequential human infections by DENV and ZIKV. The development of a simple and inexpensive assay also enables the differentiation of DENV and ZIKV infections based on characterization of T cell responses. Our T cell data reveal strong response patterns that are similar in nature to those seen with individuals with one or multiple DENV infections and with individuals with only primary ZIKV infection and ZIKV-infected individuals with previous DENV exposure. The characterization of T cell responses in a serologically validated group of individuals is of relevance to the development of vaccines and immunotherapeutics against these global threats.\n                  <\/jats:p>","DOI":"10.1128\/mbio.00755-18","type":"journal-article","created":{"date-parts":[[2018,8,6]],"date-time":"2018-08-06T05:54:49Z","timestamp":1533534889000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":14,"title":["T Cell Responses to Nonstructural Protein 3 Distinguish Infections by Dengue and Zika Viruses"],"prefix":"10.1128","volume":"9","author":[{"given":"Bobby Brooke","family":"Herrera","sequence":"first","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Yang","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Brites","sequence":"additional","affiliation":[{"name":"Laboratory of Infection Research, School of Medicine, Federal University of Bahia, Salvador, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Estela","family":"Luz","sequence":"additional","affiliation":[{"name":"Laboratory of Infection Research, School of Medicine, Federal University of Bahia, Salvador, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celia","family":"Pedroso","sequence":"additional","affiliation":[{"name":"Laboratory of Infection Research, School of Medicine, Federal University of Bahia, Salvador, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Felix","family":"Drexler","sequence":"additional","affiliation":[{"name":"Charit\u00e9 Universitatsmedizin Berlin, corporate member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Institute of Virology, Berlin, Germany"},{"name":"German Centre for Infection Research, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Kung","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Tropical Medicine, Medical Microbiology and Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, Hawaii, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phyllis J.","family":"Kanki","sequence":"additional","affiliation":[{"name":"Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Fields virology","author":"Peirson TC","year":"2013","unstructured":"Peirson TC, Diamond MS. 2013. Flaviviruses. In Knipe DM, Howley PM, Cohen JI, Griffin DE, Lamb RA, Martin MA, Racaniello VR, Roizman B (ed), Fields virology, 6th ed. Lippincott Williams & Wilkins, Philadelphia, PA.","edition":"6"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature12060"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002636"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0035-9203(64)90201-9"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.antiviral.2016.03.010"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1002203"},{"key":"e_1_3_2_8_2","unstructured":"World Health Organization. 2016. WHO Director-General summarizes the outcome of the Emergency Committee regarding clusters of microcephaly and Guillain-Barr\u00e9 syndrome. http:\/\/www.who.int\/mediacentre\/news\/statements\/2016\/emergency-committee-zika-microcephaly\/en\/."},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6511e1"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciw589"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01469-17"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.3201\/eid1408.080287"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cix672"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00316-08"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1089\/vbz.2005.5.137"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm6521e1"},{"key":"e_1_3_2_17_2","unstructured":"Centers for Disease Control and Prevention. 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