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

Svetlana Rabinovich, Rebecca L.R. Powell, Ross W.B. Lindsay, Maoli Yuan, Alexei Carpov, Aaron Wilson, Mary Lopez, John W. Coleman, Denise Wagner, Palka Sharma, Marina Kemelman, Kevin J. Wright, John P. Seabrook, Heather Arendt, Jennifer Martinez, Joanne DeStefano, Maria J. Chiuchiolo, Christopher L. Parks

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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 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.

Original languageEnglish
Article numbere106597
JournalPLoS ONE
Volume9
Issue number9
DOIs
StatePublished - Sep 2014
Externally publishedYes

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