The goal of Project 3 is to elucidate the immune correlates of efficacy in macaques immunized with SIV vaccines derived from the elegant Venezuelan Equine Encephalitis (VEE) virus replicon system (SIV-VRP). We previously showed that macaques immunized with an SIV vaccine derived from the Venezuelan Equine Encephalitis (VEE) virus replicon system (SIV-VRP) controlled replication of a virulent SIV intravenous challenge significantly better than mock immunized macaques. Prior to challenge, SIV-specific CD8+ CTL were easily detected in bulk cultures of PBMC, whereas serum neutralizing antibodies against the challenge virus were absent. Thus, it appeared that efficient control of SIV replication after challenge in SIV-VRP vaccinated macaques was due to vaccine elicited virus-specific CTL. To further explore this supposition, we propose to examine immune correlates of efficacy in macaques immunized with first and future generation SIV-VRP vaccines. First, we will determine which viral immunogen(s) in the first generation SIV-VRP vaccine was responsible for post-challenge control of in vivo SIV replication and characterize humoral and cellular immune responses associated with efficacy. Also, we will test SIV-VRP vaccines that contain additional CTL epitopes (in Gag and Pol) on the premise that """"""""more is better."""""""" Second, we will assess sera from SIV- VRP immunized macaques for the ability to block or dampen SIV replication using an""""""""in vivo"""""""" neutralization assay. Third, we will test an optimized SIV-VRP vaccine in combination with a purified Env subunit boost. The purpose of this experiment is to assess the role of neutralizing antibodies in vaccine efficacy. Two challenge routes (i.v and i.r.) will be used. Finally, we will combine technology and results from all 3 HIV- RAD Projects to generate the optimum SIV-VRP vaccine strategy, and this will be tested in both the SIV and SHIV models.
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