AAV vector has recently been used to deliver single chain Fv immunoadhesin (scFVI) versions of rhesus monkey antibodies with neutralizing activity against SIV. High, persisting levels of scFVI were achieved in 6 of 9 rhesus monkeys and these six exhibited a sterilizing barrier against SIV challenge. Three of the nine monkeys developed antibody responses to the scFVI that they received and these three were not protected against SIV challenge. Two different approaches will be compared for AAV vector delivery of the authentic IgG version of these scFVIs. We will determine whether delivery of authentic IgG decreases the frequency with which anti-anti responses are observed. We will determine whether AAV vector can be used to deliver dimeric secretory IgA and whether secretory IgA provides a more effective barrier to SIV infection by the mucosal route. Finally, we will determine whether antibody-dependent cellular cytotoxicity is important for the protective effects of the IgG versions of 4L6 and 5L7. Results from these experiments in rhesus monkeys will inform and guide development of analogous vectors for the prevention of HIV-1 infection in humans.

Public Health Relevance

Successful strategies have not been devised for the elicitation of antibodies with potent broadly-neutralizing activity against field strains of HIV-1. Use of AAV vector to deliver predefined antibodies with potent, broadly-neutralizing activity is a novel promising strategy for creating a sterilizing barrier to HIV-1 infection. Results from the proposed experiments in rhesus monkeys will inform and guide development of such vectors for the prevention of HIV-1 infection in humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI098446-01A1
Application #
8326890
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Schultz, Alan M
Project Start
2012-07-18
Project End
2013-05-31
Budget Start
2012-07-18
Budget End
2013-05-31
Support Year
1
Fiscal Year
2012
Total Cost
$810,091
Indirect Cost
$347,182
Name
Harvard University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115