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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Li, Yen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
Datta, Sandip K; Sabet, Mojgan; Nguyen, Kim Phung L et al. (2010) Mucosal adjuvant activity of cholera toxin requires Th17 cells and protects against inhalation anthrax. Proc Natl Acad Sci U S A 107:10638-43
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