Grant: Vaccines of the 21st Century

More than 25 years since HIV-1 was identified as the cause of AIDS, 60 million people have been infected and about half of them have died of HIV/AIDS. An effective vaccine is the only way to stop the epidemic, the failure of a series of vaccine trials based on the traditional approach demands novel ideas and avenues for HIV-1 vaccine development. The protease of HIV-1 is a small 99-amino acid aspartic enzyme that mediates the cleavage of Gag, Gag-Pol and Nef precursor polyproteins. The process is highly specific, temporally regulated and essential for the production of infectious viral particle. Since the protease cleavage sites of HIV-1 are much conserved among major subtypes of HIV-1, direct immune responses against these cleavage sites would yield two major advantages -1). The host immune response could destroy the virus before it can establish itself permanently in the host; and 2). the vaccine could force the virus to accumulate mutations at the protease cleavage sites and eliminating suitable substrates of the HIV protease thus eliminating viable virions. Unlike the traditional approach of antiprotease drug development, this strategy is to generate and direct host immune responses to target the 12 protease cleavage sites (p17/24, p24/p2, p2/p7, p7/p1, p1/p6, p7/TFP, TFP/p6, P6/PR,PR/RTp51, RT/RTp66,RTp66/INT, NEF) and eliminate virus by destroy viral infected cells and force the virus to mutate to its disadvantage. We propose to use Cynomolgus Macaques and SIVmac239 as an experimental model and a cocktail of peptides overlapping 12 protease cleavage sites as immunogens and deliver the peptides using two different approaches - 1). Deliver the peptides with a unique vector system (based on vesicular stomatitis virus) capable of targeting dendritic cells and generate robust immune responses; and 2). Deliver the peptide cocktail to the mucosal surface with a nanostructure delivery system.