In the classical approach to immunization against viral diseases, viral proteins are delivered or expressed in the vaccine recipient and it is hoped that the resultant immune responses are protective. For a variety of reasons, such a classic approach faces severe obstacles to success against HIV-1. The Desrosiers laboratory has been investigating a nonclassical approach by which a viral vector, adeno-associated virus (AAV), is used to achieve very long-term delivery of anti-HIV monoclonal antibodies (mAbs) with potent neutralizing activity against a broad spectrum of HIV-1 isolates. AAV vectors have proven safe in human testing and are currently the vector of choice for correction of hereditary enzyme/metabolism deficiencies. When delivered intramuscularly, transgene expression can continue for years, decades, probably for life, as long as the transgene product is not viewed as foreign. The vision is that a single inoculation of AAV vector making a cocktail of potent broadly-neutralizing antibodies will provide sterilizing immunity for the rest of the individual's life. Although an antibody may be viewed as a ?self? protein, studies in monkeys have revealed that a host antibody response may occur to the delivered mAb and this may severely limit the concentration of mAb that can be achieved. The Desrosiers laboratory will continue its progress toward minimizing the anti-anti problem and achieving consistent delivery of desirable antibodies using rhesus monkey models. These studies are directly targeted to facilitating development of this concept for use in humans.

Public Health Relevance

Development of a safe, effective, affordable immunization strategy against HIV-1 is the greatest public health challenge of our time. Use of AAV vector for long-term delivery of potent broadly-neutralizing antibodies is a realistic, highly-promising strategy for worldwide protection against HIV-1 transmission. However, the problem of host antibody responses to the delivered antibody will need to be overcome in order for the great promise of this approach to be realized.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI098446-06
Application #
9393962
Study Section
HIV/AIDS Vaccines Study Study Section (VACC)
Program Officer
Schultz, Alan M
Project Start
2012-07-18
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Bischof, G F; Shin, Y C; Fuchs, S P et al. (2017) Use of a gamma-2 herpesvirus as a vector to deliver antibodies to rhesus monkeys. Gene Ther 24:487-492
Martinez-Navio, José M; Fuchs, Sebastian P; Pedreño-López, Sònia et al. (2016) Host Anti-antibody Responses Following Adeno-associated Virus-mediated Delivery of Antibodies Against HIV and SIV in Rhesus Monkeys. Mol Ther 24:76-86
Fuchs, Sebastian P; Martinez-Navio, José M; Gao, Guangping et al. (2016) Recombinant AAV Vectors for Enhanced Expression of Authentic IgG. PLoS One 11:e0158009
Fuchs, Sebastian P; Desrosiers, Ronald C (2016) Promise and problems associated with the use of recombinant AAV for the delivery of anti-HIV antibodies. Mol Ther Methods Clin Dev 3:16068
Fuchs, Sebastian P; Martinez-Navio, José M; Piatak Jr, Michael et al. (2015) AAV-Delivered Antibody Mediates Significant Protective Effects against SIVmac239 Challenge in the Absence of Neutralizing Activity. PLoS Pathog 11:e1005090