Targeting Concatenated HIV Antigens to Human CD40 Expands a Broad Repertoire of Multifunctional CD4+ and CD8+ T Cells

AIDS. 2013 Aug 24;27(13):2041-51. doi: 10.1097/QAD.0b013e3283624305.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AIDS Vaccines / genetics
  • AIDS Vaccines / immunology*
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / metabolism
  • CD4-Positive T-Lymphocytes / immunology*
  • CD40 Antigens / immunology*
  • CD40 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Coculture Techniques
  • Dendritic Cells / immunology*
  • HIV Antigens / genetics
  • HIV Antigens / immunology*
  • HIV Antigens / metabolism
  • HIV-1 / genetics
  • HIV-1 / immunology*
  • Humans
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism

Substances

  • AIDS Vaccines
  • Antibodies, Monoclonal
  • CD40 Antigens
  • HIV Antigens
  • Recombinant Fusion Proteins