Abstract
Vaccinia virus (VACV) encodes an anti-apoptotic Bcl-2-like protein F1 that acts as an inhibitor of caspase-9 and of the Bak/Bax checkpoint but the role of this gene in immune responses is not known. Because dendritic cells that have phagocytosed apoptotic infected cells cross-present viral antigens to cytotoxic T cells inducing an antigen-specific immunity, we hypothesized that deletion of the viral anti-apoptotic F1L gene might have a profound effect on the capacity of poxvirus vectors to activate specific immune responses to virus-expressed recombinant antigens. This has been tested in a mouse model with an F1L deletion mutant of the HIV/AIDS vaccine candidate MVA-C that expresses Env and Gag-Pol-Nef antigens (MVA-C-ΔF1L). The viral gene F1L is not required for virus replication in cultured cells and its deletion in MVA-C induces extensive apoptosis and expression of immunomodulatory genes in infected cells. Analysis of the immune responses induced in BALB/c mice after DNA prime/MVA boost revealed that, in comparison with parental MVA-C, the mutant MVA-C-ΔF1L improves the magnitude of the HIV-1-specific CD8 T cell adaptive immune responses and impacts on the CD8 T cell memory phase by enhancing the magnitude of the response, reducing the contraction phase and changing the memory differentiation pattern. These findings reveal the immunomodulatory role of F1L and that the loss of this gene is a valid strategy for the optimization of MVA as vaccine vector.
Highlights
The search for a safe and effective HIV vaccine able to induce long-lived protective immunity has stimulated the development of recombinant live vaccine candidates with good safety and immunogenicity profiles
The magnitude of the total Gag-specific T cell response, determined as the sum of the individual responses obtained for the different peptide pools, was significantly higher in the group immunized with modified vaccinia virus Ankara (MVA)-C-DF1L than in the group immunized with DNA-C/MVA-C (p,0.001). These results indicate that deletion of F1L gene from MVA-C genome improved the magnitude of the HIV-1-specific adaptive CD8 T cell immune response and maintained the polyfunctional profile observed with the parental MVA-C
A number of unique features make poxvirus recombinants good candidates as vaccine vectors and members of the Poxviridae family are being widely used in the prevention and treatment of emergent infectious diseases and cancer, with an increasing interest focused on the highly attenuated ALVAC, MVA and NYVAC strains [42,43]
Summary
The search for a safe and effective HIV vaccine able to induce long-lived protective immunity has stimulated the development of recombinant live vaccine candidates with good safety and immunogenicity profiles. Recombinants based on the highly attenuated strain MVA expressing different HIV-1 antigens have been extensively studied in preclinical [2,3,4] and clinical trials with encouraging results [5,6,7,8,9,10,11,12]. MVA was derived from the Ankara strain of vaccinia virus (VACV) after more than 500 passages on chicken embryo fibroblast cells. During this extensive passage, six regions (approximately 31 kb) were lost from the viral genome, resulting in the deletion of a number of host-range restriction and immunomodulatory genes [13,14]. Further improvement of MVAbased vaccines with enhanced magnitude, breadth, polyfunctionality and durability of the immune response is needed
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