{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T23:33:54Z","timestamp":1789515234045,"version":"build-2803163510"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2017,7,27]],"date-time":"2017-07-27T00:00:00Z","timestamp":1501113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic infection with hepatitis C virus (HCV) afflicts 3% of the world\u2019s population and can lead to serious and late-stage liver diseases. Developing a vaccine for HCV is challenging because the correlates of protection are uncertain and traditional vaccine approaches do not work. Studies of natural immunity to HCV in humans have resulted in many enigmas. Human beings are not immunologically na\u00efve because they are continually exposed to various environmental microbes and antigens, creating large populations of memory T cells. Heterologous immunity occurs when this pool of memory T cells cross-react against a new pathogen in an individual. Such heterologous immunity could influence the outcome when an individual is infected by a pathogen. We have recently made an unexpected finding that adenoviruses, a common environmental pathogen and an experimental vaccine vector, can induce robust cross-reactive immune responses against multiple antigens of HCV. Our unique finding of previously uncharacterized heterologous immunity against HCV opens new avenues to understand HCV pathogenesis and develop effective vaccines.<\/jats:p>","DOI":"10.3390\/ijms18081626","type":"journal-article","created":{"date-parts":[[2017,7,27]],"date-time":"2017-07-27T11:28:40Z","timestamp":1501154920000},"page":"1626","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Unsolved Puzzles Surrounding HCV Immunity: Heterologous Immunity Adds Another Dimension"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1957-6371","authenticated-orcid":false,"given":"Babita","family":"Agrawal","sequence":"first","affiliation":[{"name":"Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6521-0998","authenticated-orcid":false,"given":"Shakti","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Gupta","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine &amp; Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satish","family":"Vedi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine &amp; Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rakesh","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine &amp; Pathology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7824","DOI":"10.3748\/wjg.v22.i34.7824","article-title":"Global epidemiology of hepatitis C virus infection: An up-date of the distribution and circulation of hepatitis C virus genotypes","volume":"22","author":"Petruzziello","year":"2016","journal-title":"World J. Gastroenterol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"12510","DOI":"10.3748\/wjg.v21.i43.12510","article-title":"Hepatitis C eradication: A long way to go","volume":"21","author":"Waheed","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1136\/gut.50.1.100","article-title":"Epidemiology and economic burden of viral hepatitis: An observational population based study","volume":"50","author":"Steinke","year":"2002","journal-title":"Gut"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3418","DOI":"10.3748\/wjg.v20.i13.3418","article-title":"Adaptive immune response during hepatitis C virus infection","volume":"20","author":"Larrubia","year":"2014","journal-title":"World J. Gastroenterol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/nsr\/nwv040","article-title":"Hepatitis C virus vaccine development: Old challenges and new opportunities","volume":"2","author":"Li","year":"2015","journal-title":"Natl. Sci. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e193","DOI":"10.1038\/ctg.2016.50","article-title":"Hepatitis C Treatment and Barriers to Eradication","volume":"7","author":"Konerman","year":"2016","journal-title":"Clin. Transl. Gastroenterol."},{"key":"ref_7","first-page":"e79","article-title":"Progress towards a hepatitis C virus vaccine","volume":"2","author":"Law","year":"2013","journal-title":"Emerg. Microbes Infect."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1146\/annurev.micro.58.030603.123836","article-title":"Cell-mediated immunity and the outcome of hepatitis C virus infection","volume":"58","author":"Shoukry","year":"2004","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.3748\/wjg.v13.i17.2436","article-title":"Epidemiology of hepatitis C virus infection","volume":"13","author":"Alter","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.jhep.2016.04.030","article-title":"Factors associated with spontaneous clearance of chronic hepatitis C virus infection","volume":"65","author":"Bulteel","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1086\/500938","article-title":"High rate of spontaneous negativity for hepatitis C virus RNA after establishment of chronic infection in Alaska Natives","volume":"42","author":"Scott","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1093\/infdis\/jir835","article-title":"Spontaneous clearance of chronic hepatitis C virus infection is associated with appearance of neutralizing antibodies and reversal of T-cell exhaustion","volume":"205","author":"Raghuraman","year":"2012","journal-title":"J. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1093\/intimm\/dxm121","article-title":"Priming and stimulation of hepatitis C virus-specific CD4+ and CD8+ T cells against HCV antigens NS4, NS5a or NS5b from HCV-naive individuals: Implications for prophylactic vaccine","volume":"20","author":"Li","year":"2008","journal-title":"Int. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/1743-422X-9-76","article-title":"Hepatitis C virus-specific cellular immune responses in individuals with no evidence of infection","volume":"9","author":"Montange","year":"2012","journal-title":"Virol. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"8304","DOI":"10.1128\/JVI.00539-15","article-title":"Frequency, private specificity, and cross-reactivity of preexisting hepatitis C virus (HCV)-specific CD8+ T cells in HCV-seronegative individuals: Implications for vaccine responses","volume":"89","author":"Zhang","year":"2015","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1002\/hep.21081","article-title":"The influence of T cell cross-reactivity on HCV-peptide specific human T cell response","volume":"43","author":"Kennedy","year":"2006","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1002\/eji.200636783","article-title":"Differential capacity of T cell priming in naive donors of promiscuous CD4+ T cell epitopes of HCV NS3 and Core proteins","volume":"37","author":"Castelli","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/nm1353","article-title":"A T-cell HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees","volume":"12","author":"Folgori","year":"2006","journal-title":"Nat. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11392","DOI":"10.1128\/JVI.75.23.11392-11400.2001","article-title":"Cross-reactivity between hepatitis C virus and Influenza A virus determinant-specific cytotoxic T cells","volume":"75","author":"Wedemeyer","year":"2001","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.jhep.2006.07.023","article-title":"Hepatitis A virus infection suppresses hepatitis C virus replication and may lead to clearance of HCV","volume":"45","author":"Deterding","year":"2006","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s15010-007-7204-7","article-title":"Clearance of chronic HCV infection during acute delta hepatitis","volume":"37","author":"Deterding","year":"2009","journal-title":"Infection"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1111\/j.1365-2893.2009.01144.x","article-title":"Virological and clinical characteristics of delta hepatitis in Central Europe","volume":"16","author":"Heidrich","year":"2009","journal-title":"J. Viral Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.coviro.2016.01.005","article-title":"Hepatitis C virus infection from the perspective of heterologous immunity","volume":"16","author":"Cornberg","year":"2016","journal-title":"Curr. Opin. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"15669","DOI":"10.1073\/pnas.202608199","article-title":"Genomic analysis of the host response to hepatitis C virus infection","volume":"99","author":"Su","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1099\/vir.0.003087-0","article-title":"Adenoviruses: Update on structure and function","volume":"90","author":"Russell","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1016\/j.vaccine.2009.12.047","article-title":"Heterologous HIV-based lentiviral\/adenoviral vectors immunizations result in enhanced HIV-specific immunity","volume":"28","author":"Asefa","year":"2010","journal-title":"Vaccine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1089\/hum.2013.235","article-title":"Adenovirus-based vaccines for fighting infectious diseases and cancer: Progress in the field","volume":"25","author":"Majhen","year":"2014","journal-title":"Hum. Gene Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4222","DOI":"10.1128\/JVI.02407-10","article-title":"Recombinant adenovirus serotype 26 (Ad26) and Ad35 vaccine vectors bypass immunity to Ad5 and protect nonhuman primates against ebolavirus challenge","volume":"85","author":"Geisbert","year":"2011","journal-title":"J. Virol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"261ra153","DOI":"10.1126\/scitranslmed.3009185","article-title":"A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts and sustains functional HCV specific T-cell memory","volume":"6","author":"Swadling","year":"2014","journal-title":"Sci. Transl. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/j.vaccine.2009.10.091","article-title":"Adenovirus-specific human T cells are pervasive, polyfunctional, and cross-reactive","volume":"28","author":"Hutnicka","year":"2010","journal-title":"Vaccine"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6065","DOI":"10.4049\/jimmunol.176.10.6065","article-title":"Induction of primary human T cell responses against hepatitis C virus-derived antigens NS3 or core by autologous dendritic cells expressing hepatitis C virus antigens: Potential for vaccine and immunotherapy","volume":"176","author":"Li","year":"2006","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Samrat, S.K., Li, W., Singh, S., Kumar, R., and Agrawal, B. (2014). Alternate reading frame protein (F protein) of hepatitis C virus: Paradoxical effects of activation and apoptosis on human dendritic cells lead to stimulation of T cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086567"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1111\/j.0105-2896.2010.00897.x","article-title":"Heterologous immunity between viruses","volume":"235","author":"Welsh","year":"2010","journal-title":"Immunolog. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Singh, S., Vedi, S., Samrat, S.K., Li, W., Kumar, R., and Agrawal, B. (2016). Heterologous immunity between adenoviruses and hepatitis C virus: A new paradigm in HCV immunity and vaccines. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0146404"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1016\/S0264-410X(02)00456-5","article-title":"Vaccination with an adenoviral vector encoding hepatitis C virus (HCV) NS3 protein protects against infection with HCV-recombinant vaccinia virus","volume":"21","author":"Arribillaga","year":"2002","journal-title":"Vaccine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1016\/j.vaccine.2009.12.037","article-title":"HCV-core and NS3 antigens play disparate role in inducing regulatory or effector T cells in vivo: Implications for viral persistence or clearance","volume":"28","author":"Krishnadas","year":"2010","journal-title":"Vaccine"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2712","DOI":"10.1016\/j.vaccine.2014.02.080","article-title":"Recombinant adenoviral vector expressing HCV ns4 induce protective immune responses in a mouse model of vaccinia-HCV virus infection: A dose and route conundrum","volume":"32","author":"Singh","year":"2014","journal-title":"Vaccine"},{"key":"ref_38","first-page":"412","article-title":"Immunization with recombinant adenoviral vectors expressing HCV core or F proteins leads to T cells with reduced effector moleculs Granzyme B and IFN-g: A potential new strategy for immune evasion in HCV infection","volume":"27","author":"Samrat","year":"2014","journal-title":"Viral Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nri3279","article-title":"Why must T cells be cross-reactive?","volume":"12","author":"Sewell","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nri820","article-title":"No one is na\u00efve: Significance of heterologous T cell immunity","volume":"2","author":"Welsch","year":"2002","journal-title":"Nat. Rev. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1615\/CritRevImmunol.v32.i4.50","article-title":"Cross-reactivity of T cells and its role in the immune system","volume":"32","author":"Petrova","year":"2012","journal-title":"Crit. Rev. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/j.immuni.2009.12.002","article-title":"The multiple mechanisms of T cell cross-reactivity","volume":"31","author":"Yin","year":"2009","journal-title":"Immunity"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.jmb.2011.10.006","article-title":"Disparate degrees of hypervariable loop flexibility control T cell receptor cross-reativity, specificity and binding mechanisms","volume":"414","author":"Scott","year":"2011","journal-title":"J. Mol. Biol."},{"key":"ref_44","first-page":"1","article-title":"Evaluation of assay methods and false positive results in the laboratory diagnosis of hepatitis C virus infection","volume":"2","author":"Kasli","year":"2011","journal-title":"Arch. Clin. Microbiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1080\/21645515.2016.1165908","article-title":"Adenoviral vector-based strategies against infectious disease and cancer","volume":"12","author":"Zhang","year":"2016","journal-title":"Hum. Vaccines Immunother."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/8\/1626\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:44:14Z","timestamp":1760208254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/8\/1626"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,27]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2017,8]]}},"alternative-id":["ijms18081626"],"URL":"https:\/\/doi.org\/10.3390\/ijms18081626","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,27]]}}}