Optimizing Adeno-Associated Virus Delivery of Anti-HIV Broadly Neutralizing Monoclonal Antibodies by Engineering an Immunomodulatory AAV Viral Vector
Abstract
Despite the discovery of HIV over 35 years ago, we have yet to develop a protective vaccine. Due to the quick rates of change and variability from one person?s virus to another, traditional vaccine approaches will not be sufficient to protect against HIV. To address this issue, several labs, including ours, have been developing an alternative approach to vaccination using a virus called adeno-associated virus (AAV). AAV is known to be safe and not cause disease in humans. It can be altered to express antibodies known to bind and neutralize almost all HIV types. When AAV is injected into muscle, it enters muscle cells and induces secretion of these antibodies. These antibodies can then confer protection to HIV and potentially even work as a therapy for people already infected with HIV. As promising as this technology is, there is one hurdle researchers have yet to overcome. Unfortunately, when tested in monkeys, delivery is not consistent. Sometimes the monkey?s immune system recognizes these antibodies as foreign and targets them for destruction. Although the pathway and mediators of this recognition have been known for over 10 years, researchers have yet to overcome it. To enhance this vaccination strategy, we propose to modify the AAV virus to now express factors known as shRNA that will inhibit the mediators critical for recognition and destruction of our delivered antibody. These mediators are MyD88, TLR9, IFN-alpha, and IFN-beta. Our lab has already identified and tested shRNA that would be ideal to inhibit MyD88, TLR9, IFN-alpha, and IFN-beta and include in the AAV virus. We propose to add these shRNAs to AAV vector, grow our new virus, and test on the cell type known to recognize the delivered antibody as foreign. If the data looks encouraging, we propose to vaccinate rhesus monkeys with our new AAV virus. We will monitor the amounts of delivered antibody in their blood as well as the immune response against the delivered antibody. By comparing monkeys that received the old version of AAV to the new version, we will be able to determine if there is any added benefit to adding shRNA to the AAV. We believe that by including these specific shRNA to our AAV vaccine we will see better delivery of our antibody as well as less immune recognition and destruction of our delivered antibody. If successful, this study will pave the way for better delivery of anti-HIV antibodies. Currently, the immune system?s recognition of AAV-delivered antibodies as foreign is the only limitation to this technology. Once this issue is solved, AAV delivery of broadly neutralizing antibodies will likely represent a protective vaccine and functional cure for HIV. This project addresses the following Fiscal Year 2018 Peer Reviewed Medical Research Program Topic Area: Vaccine Development for Infectious Disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910082
Entities
People
- James Termini
Organizations
- United States Army
- University of Miami