The full-length single chain (FLSC) immunogen is a genetically linked HIV envelope-CD4 complex which replicates a transition state that all HIV isolates must pass through during infection. Continued development of this vaccine concept requires that the immunogen demonstrate three key features. First, the immunogen must be safe. Second, the neutralizing immune response must be directed against HIV virus or a transition state structure that forms during viral entry. Third, immunization with FLSC must demonstrate efficacy. While the antibody specificity and safety can be investigated in animal models, preclinical demonstration of efficacy with HIV based FLSC immunogens is limited by the current SHIV-based animal models. Fortunately, the SIVmac virus challenge of Pigtail or Rhesus macaques is generally recognized as a rigorous primate lentiviral model that mimics the clinical and pathogenic features of human HIV infection. For this reason, this model has been utilized extensively to evaluate potential HIV vaccine concepts. We have developed a SIVmac239-based FLSC, mFLSC(239), with the goal to evaluate the FLSC vaccine concept in this challenge model. Unfortunately, the limited availability of Pigtail and Rhesus macaques prevents us from performing any statistically meaningful preliminary studies in these animals. Therefore, we propose to investigate the safety and immunogenicity of the mFLSC(239) in a related macaque species, Macaco fascicularis or cynomologus macaque, as the next step to reaching our goal. Our hypothesis is that mFLSC(239) can induce a broadly neutralizing antibody response that is SFV specific, and is not deleterious to CD4+ cells. We will test this hypothesis in three aims. First, to determine whether the mFLSC(239) can elicit broadly neutralizing antibodies against a wide range of SIV isolates. Second, to determine whether the induced neutralizing antibody response is specific for the SIV envelope, or macaque CD4 (mCD4). Third, to determine whether the mFLSC(239) induces potentially deleterious auto-anti-CD4 antibodies. Successful demonstration of the hypothesis in this exploratory setting would lay the foundation for further, more detailed, safety studies, as well as challenge experiments with SIVmac239 and heterologous SIV isolates.
