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154 Inclusion of Vpr Accessory Gene Plasmid with Vaccines Encoding Multiple HIV-1 Antigens Markedly Reduces Vaccine Effectiveness and Antigen-Specific Effector T-Cell Function in Vivo Resulting in CD4 Cell Loss and Increased Viral Loads in Rhesus Macaques
K. Muthumani1, V. Ayyavoo4, D. Conway3, S. Kudchodkar1, D. Zhang1, J. Kim6, J. Boyer1, L. Montaner2, K. Manson5, M. Bagarazzi3, and D. Weiner*1
1Univ. of Pennsylvania, Philadelphia, USA; 2The Wistar Inst., Philadelphia, PA, USA; 3St. Christopher’s Hosp. for Children, Philadelphia, PA, USA; 4Univ. of Pittsburgh, Pittsburgh, PA, USA; 5Primedica, Inc. Worcester, MA, USA; and 6Viral Genomix, Philadelphia, PA, USA
We compared the immunogenicity of plasmid vaccines containing multiple HIV antigens and found that covaccination with plasmids expressing HIV-1 14-kDa Vpr gene product profoundly reduces antigen-specific CD8-mediated cytotoxic T-cell activity (CTL). Th1 type responses against the codelivered antigens (gag/pol, nef, etc.) encoded by the plasmid vaccines were suppressed. This suggested that Vpr might compromise CD8 T-cell immunity in vivo during infection. A pilot primate vaccine study was designed to test the hypothesis to compare the following groups: unvaccinated controls, animals vaccinated with SIV antigen plasmids, and animals covaccinated with the identical SIV plasmid antigens and a plasmid construct encoding Vpr. Animals were subsequently challenged intrarectally with pathogenic SIVmac251 after the final vaccination of a multiple immunization protocol. Control animals all were infected and exhibited high viral loads and rapid CD4+ T-cell loss. In contrast, the HIV antigen plasmid-vaccinated animals exhibited preservation of CD4+ T cells, as well as CD4/CD8 T-cell ratios, preservation of the CDw29+ subset, and a multi-log reduction in viral load compared with controls was also observed. Animals covaccinated with HIV antigen vaccine plus Vpr plasmid suffered rapid and profound loss of CD4+ T cells and a dramatic inversion of the CD4/CD8 T-cell ratio. We next engineered Vpr into an Adenoviral vector and again observed suppression of vector-induced immunity. This study illustrates a marked effect of Vpr on effector host immune responses in vivo. 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 in vivo.
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