ABSTRACT: This proposal seeks to test a novel hypothesis and approach towards a vaccine to prevent HIV. We recently demonstrated efficacy against infection against pathogenic SIVmac251 challenge using an accessory antigen vaccine and MHC-II presentation system. Initially we proposed that by using a novel and innovative vaccine design based entirely on conserved accessory antigens, and a novel MHC vectored system that we could achieve protection from pathogenic SIV infection. Our success using these accessory antigens alone was remarkable, but not total, as 4/6 animals eventually became infected despite vaccination. However, we now have amassed evidence that our only mistake was to include tat in the original vaccine, which we now suspect is (like HIV env and gag) produced in abundance in acute infection to “decoy” and thwart the initial immune responses to infection, as well as induce pro-inflammatory and type 1 immune response which actually serve to benefit primary and sustained chronic HIV infection by amplifying the target cells necessary for successful HIV transmission, and to exhaust or eliminate the most sensitive structural antigen specific T cell precursors. Not only does this hypothesis explain how HIV infection occurs and is closely followed by a massive T cell activation, it also explains why the infection results in chronic immune activation, why vaccine responses to Gag, Tat, or Env are inevitably ineffective, and also why the immune system cannot regain the control of HIV infection either naturally or after prolonged antiretroviral treatment. If our hypothesis is correct, this may have dogma changing implications and may lead to an effective vaccine. Our scientific premise is that prior vaccine candidates have failed mainly because immune responses directed against early and abundantly produced Gag, Env, and Tat are detrimental to the host, and in fact supportive of viral replication, as they promote proinflammatory responses that support infection with this CD4+ T cell tropic virus, and induce primary immune responses to irrelevant antigens. Here we propose that a vaccine designed entirely using subdominant antigens and antigen fragments that are not “cross presented” (Rev, Vpr, Vif, and a conserved Env region) presented using an innovative MHC-II presentation strategy, and therefore not exhausted or contributing to excessive inflammation during acute infection, may overcome these viral mechanisms, resulting in a protective vaccine that could be effective against all HIV clades and strains.