Targeting HIV-1 Env gp140 to LOX-1 Elicits Immune Responses in Rhesus Macaques

Gerard Zurawski 1 Sandra Zurawski 2 Anne-Laure Flamar 2 Laura Richert 3, 4 Ralf Wagner 5 Georgia D. Tomaras 6 David C. Montefiori 7 Mario Roederer 8 Guido Ferrari 7 Christine Lacabaratz 9 Henri Bonnabau 4 Peter Klucar 2 Zhiqing Wang 10 Kathryn E. Foulds 8 Shing-Fen Kao 11 Nicole L. Yates 12 Celia Labranche 7 Bertram L. Jacobs 13 Karen Kibler 14 Benedikt Asbach 5 Alexander Kliche 5 Andres Salazar 15 Steve Reed 16 Steve Self 17 Raphael Gottardo 17 Lindsey Galmin 18, 19 Deborah Weiss 20 Anthony Cristillo 18 Rodolphe Thiebaut 21 Giuseppe Pantaleo 22 Yves Levy 23, 24
Abstract : Improved antigenicity against HIV-1 envelope (Env) protein is needed to elicit vaccine-induced protective immunity in humans. Here we describe the first tests in non-human primates (NHPs) of Env gp140 protein fused to a humanized anti-LOX-1 recombinant antibody for delivering Env directly to LOX-1-bearing antigen presenting cells, especially dendritic cells (DC). LOX-1, or 1ectin-like oxidized low-density lipoprotein (LDL) receptor-1, is expressed on various antigen presenting cells and endothelial cells, and is involved in promoting humoral immune responses. The anti-LOX-1 Env gp140 fusion protein was tested for priming immune responses and boosting responses in animals primed with replication competent NYVAC-KC Env gp140 vaccinia virus. Anti-LOX-1 Env gp140 vaccination elicited robust cellular and humoral responses when used for either priming or boosting immunity. Co-administration with Poly ICLC, a TLR3 agonist, was superior to GLA, a TLR4 agonist. Both CD4+ and CD8+ Env-specific T cell responses were elicited by anti-LOX-1 Env gp140, but in particular the CD4+ T cells were multifunctional and directed to multiple epitopes. Serum IgG and IgA antibody responses induced by anti-LOX-1 Env gp140 against various gp140 domains were cross-reactive across HIV-1 clades; however, the sera neutralized only HIV-1 bearing sequences most similar to the clade C 96ZM651 Env gp140 carried by the anti-LOX-1 vehicle. These data, as well as the safety of this protein vaccine, justify further exploration of this DC-targeting vaccine approach for protective immunity against HIV-1.
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Gerard Zurawski, Sandra Zurawski, Anne-Laure Flamar, Laura Richert, Ralf Wagner, et al.. Targeting HIV-1 Env gp140 to LOX-1 Elicits Immune Responses in Rhesus Macaques. PLoS ONE, Public Library of Science, 2016, 11 (4), ⟨10.1371/journal.pone.0153484⟩. ⟨hal-01389087⟩



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