Overcoming preexisting antibodies to recombinant AAV vectors in rhesus macaques

Project Summary/Abstract Delivery of potent and broadly neutralizing antibodies with recombinant adeno-associated virus vectors (AAV) is a promising approach for both, the prevention and treatment of HIV. Recombinant AAV has an outstanding safety record in over 200 clinical trials and gene delivery mediated by AAV can result in continuous durable expression of the transgene product. However, because of prior exposure to naturally circulating wild-type AAVs, a significant portion of the human population has antibodies to the AAV capsid proteins in circulation. These preexisting capsid antibodies can prevent cell transduction after recombinant AAV vector administration, jeopardizing the applicability of this approach. To overcome this crucial issue, we propose a set of approaches aimed at exerting a profound but transient depletion in vivo of circulating IgGs in AAV-positive macaques (Aim 1). AAV-mediated delivery of an anti-HIV antibody will then be assessed during such transient depletion. Our goal is to obtain consistent and robust AAV-mediated delivery of anti-HIV antibodies with independence of the capsid serostatus. If successful, the proposed strategies to overcome preexisting AAV antibodies could be a key factor in the development of future AAV-gene delivery applications and more specifically in the fight against HIV. By overcoming preexisting AAV capsid antibodies, we aim at making the AAV-delivery of antibodies a safe and reliable approach against HIV. If satisfactory delivery methods are found, it becomes possible to envision a) long-term control of the viral loads in the absence of antiretroviral treatment by delivering a combination of potent and broadly neutralizing antibodies in people and b) long-lasting protection when this approach is used in a prophylactic setting.