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155 Plasmid Vaccines Encoding SIV gag/pol and env/rev Control Viral Load and Protect CD4 T Cells from Mucosal SIV251 Challenge of Rhesus Macaques
M. Bagarazzi*2, K. Muthumani1, D. Conway2, S. Kudchodkar1, J. Kim3, J. Boyer1, and D. Weiner1
1Univ. of Pennsylvania, Philadelphia, USA; 2MCP Hahnemann Univ., Philadelphia, PA, USA; and 3Viral Genomix, Philadelphia, PA, USA
Introduction: DNA vaccination induces cellular immunity providing an important approach to the prevention of HIV-1 infection. Primates studies have reported protection from IV challenge in a nonpathogenic chimpanzee model and partial protection in a nonpathogenic SHIV model. Most recently, gag + env plasmid vaccine with IL-2-Ig adjuvant was reported to prevent CD4 T-cell loss and control viral load following IV challenge in a pathogenic SHIV-89.6p model. These exciting results have not yet been extended to demonstrate protection in a mucosal pathogenic SIV system. A study was performed comparing irrelevant plasmid immunized controls (4 rhesus macaques) to 8 animals vaccinated with separate SIV gag/pol + env/rev plasmids to test this issue. The gag/pol vector was engineered to be rev-independent using an MPV CTE element. This element drives high levels of p27 expression in vitro. Animals were vaccinated 5 times with 100 mug of each plasmid then boosted 4 times with 500 mug of each plasmid for a total dose of 2.9 mg of each plasmid. Animals were challenged rectally with pathogenic SIVmac251 1 month after the final vaccination.
Results: All animals were infected. However, dramatic differences were noted between groups. Control animals all exhibited high viral loads and rapid CD4 T-cell loss, CD4/CD8 inversion, and rapid loss of the CDw29+ lymphocyte subset. In contrast the plasmid vaccinated animals exhibited protection from CD4 T-cell loss, CD4/CD8 T-cell inversion, and the CDw29+ subset was relatively preserved. Furthermore, viral load was dramatically suppressed in these animals with an almost 3 log reduction compared with controls. This study illustrates a marked effect of multi-component plasmid vaccines in the control of pathogenesis and viral replication in a mucosal rhesus challenge model system. These results have important implications for the design of multi-component and particle vaccines for HIV-1 as well as for our understanding of HIV/SIV pathogenesis.
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