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

PLoS One. 2016 Apr 14;11(4):e0153484. doi: 10.1371/journal.pone.0153484. eCollection 2016.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / immunology
  • Animals
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Viral / immunology
  • Antibody Specificity
  • HIV-1 / immunology*
  • Humans
  • Macaca mulatta
  • Male
  • Mice
  • Recombinant Fusion Proteins / immunology
  • Scavenger Receptors, Class E / immunology*
  • T-Lymphocytes / immunology
  • env Gene Products, Human Immunodeficiency Virus / immunology*

Substances

  • AIDS Vaccines
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Viral
  • OLR1 protein, human
  • Recombinant Fusion Proteins
  • Scavenger Receptors, Class E
  • env Gene Products, Human Immunodeficiency Virus
  • gp140 envelope protein, Human immunodeficiency virus 1

Grant support

The study was funded within the Vaccine Research Institute HIV vaccine program (ANRS/INSERM and was supported by the Investissements d’Avenir program managed by the ANR under reference ANR-10-LABX-77). Support from the Poxvirus T-cell Vaccine Consortium funded by the Bill & Melinda Gates Foundation (OPP38599) for the development of NYVAC-KC vector. Support for the ICS and antibody immune monitoring assays was provided by the Vaccine Immune Monitoring Centers (OPP1032325 & OPP1032144), and support for the statistical analysis from the Vaccine Immunology Statistical Center (OPP1032317), all part of the Collaboration for AIDS Vaccine Discovery (CAVD) funded by the Bill & Melinda Gates Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.