Final Report Summary - TIP-VAC (Explaining and Improving Efficacy of targeted Immunodeficiency Virus-like Particles against AIDS) With support from two successive, Fifth Framework EU sponsored consortia, the 'Explaining and improving efficacy of targeted immunodeficiency virus-like particles against AIDS' (TIP-VAC) project has developed a targeted immunodeficiency virus-like particle vaccine (VLP) which has the G-protein of vesicular stomatitis virus incorporated in the membrane of the particle. Incorporation of VSV-G increases uptake and presentation of VLPs by dendritic cells. A pilot vaccination experiment in the SIV/macaque model provided strong protection against challenge with a pathogenic SIV. Given the urgent need for an HIV vaccine, the potential of this innovative vaccine approach should be evaluated as quickly as possible. Therefore, the aims of the current STREP application of the consortium are: 1) to determine the efficacy of the VLPs in a larger number of animals; 2) to better understand the requirements for and the mechanisms of protection; and 3) to further improve the targeted VLPs. With HIV spreading worldwide, the need for a preventive or therapeutic vaccine is more urgent than ever before. According to the United Nations program on HIV/AIDS approximately 40 million people worldwide are infected with HIV. No HIV vaccine is yet available. Efficacy studies in humans require large cohorts, and only a single trial using recombinant gp120 surface protein has been performed with no evidence of protection. Therefore, most of our knowledge on HIV vaccines comes from animal models, particularly the infection of macaques with simian immunodeficiency viruses (SIV). Work on live-attenuated immunodeficiency viruses in non-human primate models has shown that a vaccine can provide protection from progression to AIDS even in the absence of a sterilising immunity. Thus, vaccine-induced antiviral immune responses can control immunodeficiency virus replication. A number of effector mechanisms, including neutralising antibodies and CD8+ cytotoxic T-cells are likely to contribute to protection. In addition to the live-attenuated vaccines, which for safety reasons are unlikely to be applicable in humans, a number of vaccine approaches have been studied in the SIV model. Vaccination with recombinant env proteins does not provide sufficient protection against pathogenic SIV, which is consistent with results from the human phase-III trial. Similarly, whole inactivated SIV vaccines and virus-like particles do not provide significant protection. A common feature of vaccination with recombinant viral proteins and whole inactivated viruses is injection of exogenous antigens, which predominantly leads to MHC-II-restricted cellular immune responses and production of antibodies. Expression of antigens by cells of the vaccines should lead to presentation of antigens to MHC-I and MHC-II molecules. Therefore, DNA and viral vector vaccines have been extensively studied and depending on the stringency of the challenge system various degrees of protection have been observed. Instead of using viral vector systems to induce MHC-I and MHC-II-restricted immune responses, a heterologous fusion protein was incorporated into immunodeficiency virus-like particles, which should increase uptake and presentation of exogenous antigens on MHC-I and MHC-II molecules. This might explain the initial evidence of protection from disease progression in monkeys immunized with these targeted virus-like particles.