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HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells

Wee, Edmund G. and Ondondo, Beatrice and Berglund, Peter and Archer, Jacob and McMichael, Andrew J. and Baltimore, David and ter Meulen, Jan H. and Hanke, Tomas (2017) HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells. Molecular Therapy, 25 (2). pp. 494-503. ISSN 1525-0016. PMCID PMC5368423. https://resolver.caltech.edu/CaltechAUTHORS:20170206-135937690

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Abstract

To be effective against HIV type 1 (HIV-1), vaccine-induced T cells must selectively target epitopes, which are functionally conserved (present in the majority of currently circulating and reactivated HIV-1 strains) and, at the same time, beneficial (responses to which are associated with better clinical status and control of HIV-1 replication), and rapidly reach protective frequencies upon exposure to the virus. Heterologous prime-boost regimens using virally vectored vaccines are currently the most promising vaccine strategies; nevertheless, induction of robust long-term memory remains challenging. To this end, lentiviral vectors induce high frequencies of memory cells due to their low-inflammatory nature, while typically inducing only low anti-vector immune responses. Here, we describe construction of novel candidate vaccines ZVex.tHIVconsv1 and ZVex.tHIVconsv2, which are based on an integration-deficient lentiviral vector platform with preferential transduction of human dendritic cells and express a bivalent mosaic of conserved-region T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous prime-boost regimens with chimpanzee adenovirus and/or poxvirus modified vaccinia virus Ankara (MVA) vaccines to BALB/c and outbred CD1-Swiss mice, they induced a median frequency of over 6,000 T cells/10^6splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.ymthe.2016.12.004DOIArticle
http://www.cell.com/molecular-therapy-family/molecular-therapy/abstract/S1525-0016(16)45421-3PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5368423/PubMed CentralArticle
ORCID:
AuthorORCID
Baltimore, David0000-0001-8723-8190
Additional Information:© 2017 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Open access funded by Medical Research Council. Received: June 22, 2016; Accepted: December 1, 2016; Published online: December 11, 2016. The work is jointly funded by the UK Medical Research Council and the UK Department for International Development (DFID) under the MRC/DFID concordat agreement (MRC G1001757 and MR/ N023668/1) and by Immune Design Corp. This project has received funding, in part, from the European Union Horizon 2020 Research and Innovation Programme EAVI2020 under a grant agreement (681137). T.H. and A.J.M. are Jenner Institute investigators. Author Contributions: T.H., J.H.t.M, and A.J.M. conceived the experiments; E.G.W., B.O., P.B., J.A., D.B., J.H.t.M., and T.H. designed and/or carried out the experiments and analyzed the data; and T.H. wrote the article. All authors edited the manuscript. Conflicts of Interest: T.H. and A.J.M. are the inventors on Patent Cooperation Treaty (PCT) application no. PCT/US2014/058422 concerning the tHIVconsvX immunogen. J.H.t.M., J.A., and P.B. are full-time employees and shareholders of Immune Design. D.B. is a member of the scientific advisory board and a shareholder of Immune Design.
Funders:
Funding AgencyGrant Number
Medical Research Council (UK)UNSPECIFIED
Department for International Development (UK)MRC G1001757
Department for International Development (UK)MR/ N023668/1
Immune Design Corp.UNSPECIFIED
European Research Council (ERC)681137
Subject Keywords:lentivirus vectors, HIV vaccines, conserved regions, mosaic proteins
Issue or Number:2
PubMed Central ID:PMC5368423
Record Number:CaltechAUTHORS:20170206-135937690
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20170206-135937690
Official Citation:HIV-1 Conserved Mosaics Delivered by Regimens with Integration-Deficient DC-Targeting Lentiviral Vector Induce Robust T Cells Wee, Edmund G. et al. Molecular Therapy , Volume 25 , Issue 2 , 494 - 503
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:74091
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:06 Feb 2017 22:16
Last Modified:03 Oct 2019 16:34

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