TY - JOUR
T1 - 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
AU - Rabinovich, Svetlana
AU - Powell, Rebecca L.R.
AU - Lindsay, Ross W.B.
AU - Yuan, Maoli
AU - Carpov, Alexei
AU - Wilson, Aaron
AU - Lopez, Mary
AU - Coleman, John W.
AU - Wagner, Denise
AU - Sharma, Palka
AU - Kemelman, Marina
AU - Wright, Kevin J.
AU - Seabrook, John P.
AU - Arendt, Heather
AU - Martinez, Jennifer
AU - DeStefano, Joanne
AU - Chiuchiolo, Maria J.
AU - Parks, Christopher L.
N1 - Funding Information:
IAVI9s work is made possible by generous support from many donors including: the Bill and Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID). The full list of IAVI donors is available at www.iavi.org. Award Number R01AI084840 from the National Institute of Allergy and Infectious Diseases and The Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) supported this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank our colleagues George Pavlakis and Barbara Felber for providing the expression plasmid used for construction of plasmid DNA vaccines, Beth Rasmussen for project management, and Megan Finnegan for administrative support.
Publisher Copyright:
© 2014 Rabinovich et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2014/9
Y1 - 2014/9
N2 - 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 59terminus 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 104-105, 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.
AB - 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 59terminus 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 104-105, 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.
UR - http://www.scopus.com/inward/record.url?scp=84918800853&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0106597
DO - 10.1371/journal.pone.0106597
M3 - Article
C2 - 25215861
AN - SCOPUS:84918800853
SN - 1932-6203
VL - 9
JO - PLoS ONE
JF - PLoS ONE
IS - 9
M1 - 0106597
ER -