Heteroclitic Analogs Derived from the HTLV-1 Gag Antigen Increase Cytolytic and IFN-gamma Responses in HLA-A*0201 Transgenic Mice

摘要

The Human T-cell Leukemia Virus type-1 (HTLV-1) is the etiologic agent of Adult T-cell Leukemia (ATL); HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and other inflammatory disorders. There is an increasing body of evidence demonstrating the value of CTL in controlling viral infection. HTLV-1 infected individuals with active cytolytic responses, and lowered provirus load are less likely to develop ATL or HAM/TSP. Therefore strategies aimed at improving the cytolytic properties of CTL generated in a prophylactic or therapeutic vaccine may be of value. Heteroclitic analogs (epitope enhanced peptides) with optimized MHC I anchor residues have been used to increase the immunogenicity of CTL epitopes for various viral and cancer antigens. Recently it has been demonstrated that this strategy could be used to increase the immunogenicity of CTL directed against a highly conserved, low affinity epitope derived from HIV-1 reverse transcriptase. Peptide immunogens with enhanced binding properties induce stronger MHC I-peptide-TCR interactions and therefore induce stronger activation signaling cascades, thereby increasing immunogenicity. The HTLV-1 Gag protein contains no optimal HLA-A*0201 restricted epitopes (an aromatic residue in position 1, Leu in the 2 position, and Val in the 9 position). Therefore, epitope enhancement is a feasible strategy to increase the immunogenicity of peptides against this antigen.