OPTIMIZE THE IMMUNOGENICITY OF MVA-BASED AIDS VACCINES

Emory University, Atlanta GA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The overall goal of this project is to identify strategies by which the immunogenicity of AIDS vaccines derived from MVA-based viral vectors can be significantly augmented. We previously developed and characterized an MVA-based HIV vaccine (from which four endogenous poxvirus immune-evasion genes have been deleted) that expresses consensus HIV subtype C Gag and Env antigens (MVA[unreadable]4-HIV). In MHC-disparate populations of rhesus macaques, this genetically engineered vaccine was shown to elicit significantly higher levels of HIV-specific CD8 and CD4 T cell responses and up to 25-fold higher titers of HIV envelope-specific antibodies, as compared to the unmodified parental control vaccine. Recently, we completed a study, in rhesus macaques, which demonstrated that the HIV-specific antibody responses elicited by the MVA[unreadable]4-HIV vaccine may be further augmented through an immunization regimen that includes co-administration of a TLR-9 agonist, but not a TLR-7/8 agonist, as a vaccine adjuvant. In another study of macaques immunized with MVA-based vaccines expressing SIV, rather than HIV, antigens, we took a deep pyrosequencing approach to characterize the appearance, dynamics and anatomic dissemination of CTL escape mutant viruses in lymphoid versus mucosal tissues following SIVmac239 infection. Our results indicate that lymph nodes, rather than peripheral blood mononuclear cells or rectal mucosa, represent the primary source of CTL escape mutants during the acute phase of SIV infection, suggesting that lymph nodes are the main anatomic sites of virus replication and/or the tissues in which CTL pressure is most effective in selecting SIV escape variants.