Our previous studies have shown that therapeutic DNA vaccine induction of mucosal responses correlated with significant reduction of virus in the gut of SIV-infected macaques despite the use of a suboptimal ART regimen. This vaccine stimulated T cell responses that suppressed virus to low/undetectable levels and afforded a durable "functional cure" in ~50% of the animals after stopping ART. We propose here to make therapeutic vaccination even more effective by 1) using a more potent combination of drugs (cART) to maximize the effects of the vaccine, 2) using a mucosal adjuvant (LT) to target immune responses to residual virus in gut associated lymphoid tissue, and 3) use of a novel SIV conserved elements (CE) DNA vaccine to focus T cell responses against highly conserved viral sequences that if mutated will impose greater fitness cost. Our overarching hypothesis is that vaccine-induced functional cure is mediated by strong mucosal CD8 responses, and that focusing these responses to the gut in maximally suppressed infections and against more conserved epitopes, which suppress a wider range of possible viral variants and select for more fitness-costing escape mutations, will maximally disable the ability of residual viruses to emerge from the latent reservoir after stopping cART. Operationally, using optimized cART and mucosal targeting we will compare a traditional whole antigen and a CE DNA vaccine for the ability to increase the frequency and strength of mucosal and systemic CD8 responses against conserved viral sequences, and for their impact on viral evolution and fitness, and determine the role of these factors in a functional cure.
Our specific aims are to: 1) Determine therapeutic efficacy of an LT-adjuvanted traditional SIV DNA vaccine expressing whole antigens when used with more potent cART. 2) Determine if an SIV CE immunogen will improve therapeutic efficacy. 3) Define immune and virological mechanisms underlying functional cures. Through the proposed studies we will define the virological and immune profile of a vaccine-induced functional cure and determine the feasibility of a novel CE DNA vaccine to induce a functional cure of SIV infection.

Public Health Relevance

The goal is to develop a novel therapeutic vaccine that when administered during HAART blocks resurgence of viremia after drug therapy is discontinued. If successful, this approach will provide a new frontier in HIV treatment where short-term HAART and vaccination will lead to a durable functional cure from progression to AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI104679-01A1
Application #
8606654
Study Section
Special Emphasis Panel (ZRG1-AARR-D (02))
Program Officer
Conley, Tony J
Project Start
2013-08-15
Project End
2017-07-31
Budget Start
2013-08-15
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$959,000
Indirect Cost
$402,134
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195