Despite more than two decades of extensive research, the development of an effective vaccine for HlV-1 remains elusive. A significant critical hurdle that compounds this challenge in vaccine development includes a lack of knowledge in defining the key correlate of protection against infection with HIV-1. Emerging evidence in various preclinical and clinical studies suggest a key role for HIV-1 specific neutralizing antibody responses present in high levels both systemic and at mucosal surfaces, as well as a role for polyfunctional T cell responses that can control the spread of the virus. It is now well documented that innate immunity plays a central role in shaping the quality and longevity of adaptive immune responses. Rational approaches that mediate robust activation of innate immunity and deliver HlV-1 specific antigens to key innate immune cells such as dendritic cells (DCs) could significantly enhance the magnitude, quality and persistence of ensuing humoral and T cell immunity against the HIV-1 virus. Recent studies have demonstrated that select combinations of ligands for toll like receptors (TLRs) can mediate such robust activation of DCs. Our proposal is driven by the hypothesis that such synergistic increases in DC activation would translate into synergistic enhancement in frequencies and quality of antigen specific B and T cells. Our studies in mice using a variety of protein antigens and combination of ligands for TLR-4 (MPL) and TLR-7 (R837) delivered in novel synthetic nanoparticle formulations indicate synergistic increases in antigen specific memory B cell, CD4 and CDS T cell responses, which persist for almost the life time of the animal. Furthermore, our best adjuvant chosen from mice studies when tested in non human primates with a whole inactivated 2009 H1N1 flu virus mediated robust neutralization antibody responses even with a single immunization. Collectively, these data strongly support our hypothesis that the combination of ligands for TLR-4 and TLR-7/8 could significantly enhance the quality of B cell and T cell responses against SIV antigens. Here we propose to evaluate SIV virus like particle (VLP) antigens adjuvanted with toll like receptor (TLR) ligands encapsulated in biodegradable nanoparticles in mediating protective immunity against the SIV virus in non human primates.
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