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, 1 Ralf Wagner 4 Georgia D. Tomaras 5 David C. Montefiori 5 Mario Roederer 6 Guido Ferrari 5 Christine Lacabaratz 7 Henri Bonnabau 1 Peter Klucar 2 Zhiqing Wang 8 Kathryn E. Foulds 6 Shing-Fen Kao 9 Nicole L. Yates 10 Celia Labranche 5 Bertram L. Jacobs 11 Karen Kibler 12 Benedikt Asbach 4 Alexander Kliche 4 Andres Salazar 13 Steve Reed 14 Steve Self 15 Raphael Gottardo 15 Lindsey Galmin 16 Deborah Weiss 17 Anthony Cristillo 16 Rodolphe Thiebaut 18 Giuseppe Pantaleo 19 Yves Levy 20, 21
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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