Alexander Gain, University of Western Ontario

Alexander Gain (Dept. Microbiology & Immunology, University of Western Ontario), Steven Kerfoot (Dept. Microbiology & Immunology), Eric Arts (Dept. Microbiology & Immunology)

Suppressing & Conquering

The critical role of the envelope (Env) protein of HIV-1 in viral attachment and entry makes it a key target for vaccination. Low level Env expression on the viral and infected cell surface makes recognition by the host immune system difficult. The heavily glycosylated nature of Env further impairs induction of broad-neutralizing responses by sterically blocking interactions with cognate B cells. However, we have recently identified Env mutations hindering surface glycosylation near conserved epitopes such as the CD4 binding site (CD4bs), enhancing B cell interactions. Additionally, we have discovered a unique N425K mutation which dramatically increases affinity for CD4. This study will further develop an Env-recombinant VSV vector, based on the approved Zaire Ebolavirus vaccine. We have previously found that this vector provides modest protection in mice and macaques. However, studies thus far have been limited to only a single transmitted/founder (T/F) strain: A74, and there warrants inclusion of other subtypes. Following optimization with the above, we hypothesize our VSV-HIV vector may preferentially select and expand B cells with anti-CD4bs activity, effectively neutralizing strains of wildtype HIV-1 and protect against novel infection. To address this, a two-fold method will be used: (1) a human tonsil organoid model designed to test prime and boost vaccine responses, and (2) human/murine CD4 transgenic mice. This project will identify which T/F Env-mutant combination and which vaccination strategy will best elicit protective immunity. It will justify further studies into this VSV-HIV vector and its potential use in finally developing an effective HIV-1 vaccine.