Targeting HIV-1 Env gp140 to LOX-1 Elicits Immune Responses in Rhesus Macaques.
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.
Zurawski, G; Zurawski, S; Flamar, A-L; Richert, L; Wagner, R; Tomaras, GD; Montefiori, DC; Roederer, M; Ferrari, G; Lacabaratz, C; Bonnabau, H; Klucar, P; Wang, Z; Foulds, KE; Kao, S-F; Yates, NL; LaBranche, C; Jacobs, BL; Kibler, K; Asbach, B; Kliche, A; Salazar, A; Reed, S; Self, S; Gottardo, R; Galmin, L; Weiss, D; Cristillo, A; Thiebaut, R; Pantaleo, G; Levy, Y
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