title: A novel, live-attenuated vesicular stomatitis virus vector displaying conformationally intact, functional HIV-1 envelope trimers that elicits potent cellular and humoral responses in mice.
abstract: Though vaccination with live-attenuated SIV provides the greatest protection from progressive disease caused by SIV challenge in rhesus macaques, attenuated HIV presents safety concerns as a vaccine; therefore, live viral vectors carrying HIV immunogens must be considered. We have designed a replication-competent vesicular stomatitis virus (VSV) displaying immunogenic HIV-1 Env trimers and attenuating quantities of the native surface glycoprotein (G). The clade B Env immunogen is an Env-VSV G hybrid (EnvG) in which the transmembrane and cytoplasmic tail regions are derived from G. Relocation of the G gene to the 5'terminus of the genome and insertion of EnvG into the natural G position induced a ∼1 log reduction in surface G, significant growth attenuation compared to wild-type, and incorporation of abundant EnvG. Western blot analysis indicated that ∼75% of incorporated EnvG was a mature proteolytically processed form. Flow cytometry showed that surface EnvG bound various conformationally- and trimer-specific antibodies (Abs), and in-vitro growth assays on CD4+CCR5+ cells demonstrated EnvG functionality. Neither intranasal (IN) or intramuscular (IM) administration in mice induced any observable pathology and all regimens tested generated potent Env-specific ELISA titers of 10(4)-10(5), with an IM VSV prime/IN VSV boost regimen eliciting the highest binding and neutralizing Ab titers. Significant quantities of Env-specific CD4+ T cells were also detected, which were augmented as much as 70-fold by priming with IM electroporated plasmids encoding EnvG and IL-12. These data suggest that our novel vector can achieve balanced safety and immunogenicity and should be considered as an HIV vaccine platform.
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America; Molecular and Cellular Biology Program, The School of Graduate Studies, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Rabinovich
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Rebecca L R
authors.initials: RL
authors.lastname: Powell
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Ross W B
authors.initials: RW
authors.lastname: Lindsay
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Maoli
authors.initials: M
authors.lastname: Yuan
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Alexei
authors.initials: A
authors.lastname: Carpov
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Wilson
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Lopez
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: John W
authors.initials: JW
authors.lastname: Coleman
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Denise
authors.initials: D
authors.lastname: Wagner
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Palka
authors.initials: P
authors.lastname: Sharma
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Kemelman
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Wright
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Seabrook
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Heather
authors.initials: H
authors.lastname: Arendt
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Martinez
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America.
authors.forename: Joanne
authors.initials: J
authors.lastname: DeStefano
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America; Molecular and Cellular Biology Program, The School of Graduate Studies, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Chiuchiolo
authors.affiliation: International AIDS Vaccine Initiative, Design and Development Laboratory, Brooklyn, New York, United States of America; Molecular and Cellular Biology Program, The School of Graduate Studies, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Parks
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D005260:Female; D005822:Genetic Vectors / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D007111:Immunity, Cellular / Q000276:immunology*; D056724:Immunity, Humoral / Q000276:immunology*; D007114:Immunization; D008168:Lung / Q000276:immunology; D018655:Lymphocyte Count; D008807:Mice, Inbred BALB C; D011487:Protein Conformation; D055503:Protein Multimerization; D013154:Spleen / Q000276:immunology; D014613:Vaccines, Attenuated / Q000276:immunology*; D014721:Vesicular stomatitis Indiana virus / Q000378:metabolism*; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism
chemical_list: D014613:Vaccines, Attenuated; D054299:env Gene Products, Human Immunodeficiency Virus