title: Hexon hypervariable region-modified adenovirus type 5 (Ad5) vectors display reduced hepatotoxicity but induce T lymphocyte phenotypes similar to Ad5 vectors.
abstract: Hexon modification of adenovirus type 5 (Ad5) vectors with the hypervariable regions (HVRs) of Ad48 has been shown to allow Ad5HVR48 vectors to circumvent the majority of the preexisting Ad5-neutralizing antibodies. However, it remains unclear whether modifying hexon HVRs impacts innate or adaptive immune responses elicited by this vector. In this study, we investigated the influence of the HVR substitution of Ad5 on innate and adaptive immune responses following vaccination. Ad5HVR48 displayed an intermediate level of innate immune cytokines and chemokines relative to those of Ad5 and Ad48, consistent with its chimeric nature. Hepatotoxicity was observed after Ad5 immunization but not after Ad5HVR48 or Ad48 immunization. However, the CD8(+) T-cell responses elicited by Ad5HVR48 vectors displayed a partially exhausted phenotype, as evidenced by the sustained expression of programmed death 1 (PD-1), decreased effector-to-central memory conversion, and reduced memory recall responses, similar to those elicited by Ad5 vectors and in contrast to those induced by Ad48 vectors. Taken together, these results indicate that although Ad5HVR48 largely bypasses preexisting Ad5 neutralizing antibodies and shows reduced hepatotoxicity compared to that of Ad5, it induces adaptive immune phenotypes that are functionally exhausted similar to those elicited by Ad5.
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Teigler
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Penaloza-MacMaster
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Obeng
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Provine
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Rafael A
authors.initials: RA
authors.lastname: Larocca
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
authors.forename: Erica N
authors.initials: EN
authors.lastname: Borducchi
authors.affiliation: Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts, USA dbarouch@bidmc.harvard.edu.
authors.forename: Dan H
authors.initials: DH
authors.lastname: Barouch
mesh_terms: D056704:Adaptive Immunity; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000956:Antigens, Viral / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology*; D002678:Chimera / Q000235:genetics / Q000276:immunology; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D057131:Immune Evasion / Q000276:immunology; D007113:Immunity, Innate; D007156:Immunologic Memory / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008099:Liver / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D014611:Vaccination
chemical_list: D057134:Antibodies, Neutralizing; D000956:Antigens, Viral; D036022:Capsid Proteins; D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C018315:hexon capsid protein, Adenovirus; D007371:Interferon-gamma