Control of the worldwide HIV epidemic will require development of a preventive and therapeutic HIV vaccine. An effective vaccine will need to elicit neutralizing antibodies as well as an effective CTL response. Toll-like receptor (TLR) ligands are potent activators of antigen presenting cells that are central in the development of a successful adaptive immune response. We hypothesize that using synthetic TLR ligands, such as immunostimulatory DNA, in HIV vaccine preparations will improve anti-HIV immune responses. Furthermore, inhibiting TLR-induced inhibitory pathways that down-regulate immune responses, such as IL-10 and indoleamine 2,3-dioxygenase (IDO), should further optimize immune responses. Thus, we propose to investigate: 1) the development of memory CD8+ T cell responses after TLR ligand-based vaccination with a model antigen (ovalbumin) and with inactivated SIV, characterization of the effector and central memory responses, and requirement for CD4+ T cells in the development and maintenance of memory cells; 2) the ability to augment immune responses by inhibiting IDO, a critical enzyme in tryptophan catabolism that down-regulates T cell responses, and/or by neutralizing the inhibitory cytokine IL-10 in in vitro and in vivo systems; 3) the outcome of the approaches mentioned above to elicit immune responses against SIV in mice that will be reconstructed to express the human/primate cellular expression profile of TLR9; 4) the most promising approaches selected in SA 1-3 in an in vitro and in an in vivo macaque system before and after SIV challenge; 5) the efficacy of TLR ligand-based vaccines in a human PBMC system. Specifically, the augmentation of CD4+ and CD8+ T cell memory responses to CMV in CMV+ donors after incubation with TLR ligands and inactivated CMV will be assessed as well as the effect of CD4-depletion on the anti-CMV responses and anti-HIV responses by using PBMCs from HIV+/CMV+ donors. These experiments were designed to provide a balanced investigation that explores fundamental immunology and provides the practical aspects of vaccinology that will move us closer to development of an effective HIV vaccine for humans.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058743-03
Application #
7085478
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Li, Yen
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$441,753
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Datta, Sandip K; Okamoto, Sharon; Hayashi, Tomoko et al. (2006) Vaccination with irradiated Listeria induces protective T cell immunity. Immunity 25:143-52
Datta, Sandip K; Raz, Eyal (2005) Induction of antigen cross-presentation by Toll-like receptors. Springer Semin Immunopathol 26:247-55