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* Mucosal Immunology Unit, Kings College, London, United Kingdom;
Department of Oral Medicine and Pathology, Kings College, London, United Kingdom; and
Lionex Diagnostics and Therapeutics, Braunschweig, Germany
Apolipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like-3G (A3G) is an intracellular innate antiviral factor that deaminates retroviral cytidine to uridine. In an attempt to harness the anti-HIV effect of A3G, we searched for an agent that would up-regulate A3G and identify the receptors involved. Stimulation of cell surface CCR5 with CCL3 and CD40 with CD40L or both molecules with microbial 70-kDa heat shock protein (HSP)70 up-regulated A3G mRNA and protein expression in human CD4+ T cells and monocyte-derived dendritic cells (DC), demonstrated by real-time PCR and Western blots, respectively. The specificity of CCR5 and CD40 stimulation was established by inhibition with TAK 779 and mAb to CD40, as well as using human embryonic kidney 293 cells transfected with CCR5 and CD40, respectively. A dose-dependent increase of A3G in CCL3- or HSP70-stimulated CD4+ T cells was associated with inhibition in HIV-1 infectivity. To differentiate between the inhibitory effect of HSP70-induced CCR5 binding and that of A3G, GFP-labeled pseudovirions were used to infect human embryonic kidney 293 cells, which showed inhibition of pseudovirion uptake, consistent with A3G being responsible for the inhibitory effect. Ligation of cell surface CCR5 receptors by CCL3 or CD40 by CD40L activated the ERK1/2 and p38 MAPK signaling pathways that induced A3G mRNA expression and production of the A3G protein. These in vitro results were corroborated by in vivo studies in rhesus macaques in which A3G was significantly up-regulated following immunization with SIVgp120 and p27 linked to HSP70. This novel preventive approach may in addition to adaptive immunity use the intracellular innate antiviral effect of A3G.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by European Community Grants LSHP-CT-2003-503558 and LSHP-CT-2003-503240.
2 Address correspondence and reprint requests to Dr. Thomas Lehner, Mucosal Immunology Unit, Guy’s Tower Floor 28, Guy’s Hospital, London SE1 9RT, U.K. E-mail address: thomas.lehner{at}kcl.ac.uk
3 Abbreviations used in this paper: DC, dendritic cell; A3G, apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like-3G; HEK, human embryonic kidney; HSP, heat shock protein; LMM, low molecular mass; MFI, mean fluorescence intensity; RT, reverse transcription; Vif, viral infectivity factor; VSV, vesicular stomatitis virus; ct, cycle threshold.
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