Development of an HIV vaccine using a vesicular stomatitis virus vector expressing designer HIV-1 envelope glycoproteins to enhance humoral responses

Abstract

Vesicular stomatitis virus (VSV), like many other Rhabdoviruses, have become the focus of intense research over the past couple of decades based on their suitability as vaccine vectors, transient gene delivery systems, and as oncolytic viruses for cancer therapy. VSV as a vaccine vector platform has multiple advantages over more traditional viral vectors including low level, non-pathogenic replication in diverse cell types, ability to induce both humoral and cell-mediate immune responses, and the remarkable expression of foreign proteins cloned into multiple intergenic sites in the VSV genome. The utility and safety of VSV as a vaccine vector was recently demonstrated near the end of the recent Ebola outbreak in West Africa where VSV pseudotyped with the Ebola virus (EBOV) glycoprotein was proven safe in humans and provided protective efficacy against EBOV in a human phase III clinical trial. A team of Canadian scientists, led by Dr. Gary Kobinger, is now working with International AIDS Vaccine Initiative (IAVI) in developing a VSV-based HIV vaccine that will combine unique Canadian research on the HIV-1 Env glycoprotein and on the VSV vaccine vector. The goal of this collaboration is to develop a vaccine with a robust and potent anti-HIV immune response with an emphasis on generating quality antibodies to protect against HIV challenges.

Keywords: Env antigens; HIV; Vaccine; Vesicular stomatitis virus.

Fig. 1

a Schematic drawing of the wild-type VSV genome (VSV wild-type), the VSV genome lacking the G protein (VSV∆G) and the recombinant form of the genome with the Ebola GP inserted in place of VSV G (VSV∆G/EBOVGP), along with an illustration depicting the rVSV∆G/EBOVGP vaccine vector. b Schematic drawing of the recombinant VSV genome with an HIV Env gene inserted in place of the VSV G protein, along with an illustration depicting the VSV∆G/HIVenv vaccine vector

Fig. 2

Schematic of the prefusion intermediate of VSV G glycoprotein structure (left) (PDB 5I2M) [36] and of the HIV Env gp140 structure (right) (PDB 4ZMJ) [37] in juxtaposition to a membrane

Fig. 3

Schematic of gp120 HIV-1YU-2 complexed with CD4 and 412 Ab (PDB ID: 2QAD) [38] and modeled using the COOT program to contain the N425 to K mutation in gp120. The Nε of K425 can interact with residues from CD4 including a cation-π interaction with F43 of CD4 (This model was adapted from [35])