Targeting concatenated HIV antigens to human CD40 expands a broad repertoire of multifunctional CD4+ and CD8+ T cells

OBJECTIVE: Targeting HIV antigens directly to dendritic cells using monoclonal antibodies against cell-surface receptors has been shown to evoke potent cellular immunity in animal models. The objective of this study was to configure an anti-human CD40 antibody fused to a string of five highly conserved CD4 and CD8 T-cell epitope-rich regions of HIV-1 Gag, Nef and Pol (αCD40.HIV5pep), and then to demonstrate the capacity of this candidate therapeutic vaccine to target these HIV peptide antigens to human dendritic cells to expand functional HIV-specific T cells. METHODS: Antigen-specific cytokine production using intracellular flow cytometry and multiplex bead-based assay, and suppression of viral inhibition, were used to characterize the T cells expanded by αCD40.HIV5pep from HIV-infected patient peripheral blood mononuclear cell (PBMC) and dendritic cell/T-cell co-cultures. RESULTS: This candidate vaccine expands memory CD4 and CD8 T cells specific to multiple epitopes within all five peptide regions across a wide range of major histocompatibility complex (MHC) haplotypes from HIV-infected patient PBMC and dendritic cell/T-cell co-cultures. These in vitro expanded HIV antigen-specific CD4 and CD8 T cells produce multiple cytokines and chemokines. αCD40.HIV5pep-expanded CD8 T cells have characteristics of cytotoxic effector cells and are able to kill autologous target cells and suppress HIV-1 replication in vitro. CONCLUSION: Our data demonstrate the therapeutic potential of this CD40-targeting HIV candidate vaccine in inducing a broad repertoire of multifunctional T cells in patients.