Wednesday, April 24, 2024
4/24/2024
Project Summary/Abstract The poor immunogenicity of the HIV envelope spike and its vast variability represent major obstacles for efficient elicitation of protective anti-HIV antibodies. One promising strategy is to bypass the immune system and deliver already known and well-characterized potent and broadly neutralizing antibodies directly to the host. However, periodic administrations of large amounts of protein would be required for long-term effects. Recombinant adeno- associated virus (AAV) vectors have been widely used for gene delivery applications because of their safety and cost-efficiency: one single injection can account for long term expression of the transgene. The use of AAV vectors would bypass the need for periodic administrations of antibody and, as long as the delivered protein is viewed as self, it can result in continuous durable expression. Studies in monkeys and in mice have already shown the extreme promise of AAV for this antibody delivery approach against HIV, and pioneer human trials have demonstrated its safety and feasibility. However, only antibodies in IgG form (monomeric immunoglobulin) have been employed in such AAV-antibody delivery applications, while polymeric immunoglobulins (such as dimeric IgA and pentameric IgM) have been overlooked, despite their desirable characteristics for mucosal protection. In addition, little is known about what proportion of circulating AAV-delivered antibody gets transferred to relevant viral entry points such as the rectal or vaginal mucosae and how that correlates with the level of protection against mucosal exposure that can be achieved. Building up on our previous monkey trials, what we propose here is to evaluate AAV-mediated delivery of a potent and broadly neutralizing antibody as different immunoglobulin types and assess the degree of protection that can be achieved to mucosal viral challenge by each type (Aim 1). We will use the highly relevant macaque model and quantitate in vivo AAV-produced antibody in circulation and in the relevant mucosae. Our goal is to find what immunoglobulin type shows optimal transfer of the AAV-delivered antibody to the viral point of entry in mucosae and/or optimal protection against challenge. Because HIV is mainly transmitted sexually, our findings will be highly relevant in the fight against HIV transmission. Our overall goal is to inform and guide development of the AAV-antibody concept for its use in people.
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