Thirty years into the AIDS epidemic, there are an estimated 34 million HIV-infected people worldwide and almost 70% reside in sub-Saharan Africa. Although intensive research towards developing an AIDS vaccine is continuing, there are as yet no effective HIV vaccines on the horizon. For a HIV vaccine to be successful, it is widely accepted that it should be able to induce mucosal immunity, elicit an effective cytolytic and polyfunctional HIV-specific T cell response along with anti-HIV antibodies that have broadly directed neutralization activity and antibody dependent cellular cytotoxicity (ADCC) activity. The innate immune system is an important modulator of adaptive immunity and can shape the magnitude, quality, and durability of pathogen-specific immune responses at systemic and mucosal sites. Natural killer T (NKT) cells are unique T cells of the innate immune system with potent immunoregulatory properties that can impact T and B cell immunity. In this grant application we propose to use the SIV infection macaque model to investigate the hypothesis that NKT activation will improve vaccine immunogenicity and improve vaccine-mediated protection against acquisition and control of SIV infection. Conversely, the absence of NKT cells may reduce the efficacy of a protective live attenuated SIV (LASIV) vaccine.
Our specific aims are: #1. Determine the optimal dosing regimen for in vivo administration of the NKT-depleting and NKT-activating mAbs and characterize their effect in blood and tissues of cynomolgus macaques. #2. Investigate the hypothesis that the adjuvant effect of NKT activation will enhance the protective efficacy of a heterologous prime-boost recombinant Ad26/Ad5-SIV vaccine regimen. #3. Investigate the hypothesis that vaccination in the setting of NKT depletion will abrogate the protective efficacy of a highly protective LASIV vaccine.

Public Health Relevance

Natural killer T (NKT) cells are innate immune cells with potent immunoregulatory properties that can shape host immune responses against a variety of pathogens. In this project we will investigate whether NKT cell activation can act as an adjuvant to enhance the protective efficacy of a candidate AIDS vaccine. Strategies to improve vaccine efficacy are a step forward towards development of a safe and effective HIV vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI102693-04
Application #
9022675
Study Section
Special Emphasis Panel (ZAI1-DR-A (M2))
Program Officer
Dang, Que
Project Start
2012-06-19
Project End
2016-05-31
Budget Start
2015-04-08
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$690,636
Indirect Cost
$273,810
Name
Tulane University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118