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

Flamar, Anne-Laurea,b,c,d; Xue, Yaminga; Zurawski, Sandra M.a,b,d; Montes, Monicaa,b,d; King, Bryane; Sloan, Louise; Oh, SangKona,d; Banchereau, Jacquesa,b,d; Levy, Yvesb,f,g; Zurawski, Gerarda,b,d

doi: 10.1097/QAD.0b013e3283624305
Basic Science

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.

aBaylor Institute for Immunology Research, Dallas, Texas, USA

bANRS HIV Vaccine Network/Vaccine Research Institute, Paris

cEcole doctorale Sciences de la Vie et de la Santé, Université Paris-Est, Créteil, France

dINSERM U899

eNorth Texas Infectious Diseases, Dallas, Texas, USA

fUniversité Paris-Est, Faculté de Médecine, INSERM U955

gAssistance Publique-Hôpitaux de Paris, Groupe Henri-Mondor Albert-Chenevier, service d’immunologie clinique, Créteil, France.

Correspondence to Gerard Zurawski, PhD, Baylor Institute for Immunology Research, 3434 Live Oak Street, Dallas, Texas, 75204, USA. Tel: +1 214 557 9089; fax: +1 214 820 4813; e-mail: gerardz@baylorhealth.edu

Received 26 August, 2012

Revised 21 February, 2013

Accepted 11 April, 2013

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© 2013 Lippincott Williams & Wilkins, Inc.