TY - JOUR
T1 - A cinnamon-derived procyanidin compound displays anti-HIV-1 activity by blocking heparan sulfate- and co-receptor- binding sites on gp120 and reverses T cell exhaustion via impeding Tim-3 and PD-1 upregulation
AU - Connell, Bridgette Janine
AU - Chang, Sui Yuan
AU - Prakash, Ekambaranellore
AU - Yousfi, Rahima
AU - Mohan, Viswaraman
AU - Posch, Wilfried
AU - Wilflingseder, Doris
AU - Moog, Christiane
AU - Kodama, Eiichi N.
AU - Clayette, Pascal
AU - Lortat-Jacob, Hugues
N1 - Funding Information:
This work was supported by Indus Biotech and the Agence Nationale de la Recherche sur le SIDA (ANRS). B.J.C. was supported by a grant from Sidaction and "la Fondation Pierre Berg?". SYC acknowledges the funding from National Science Council (NSC), Taiwan. This work also used the platforms of the Grenoble Instruct centre supported by the Agence Nationale de la Recherche (ANR-10-INSB-05-02 and ANR-10-LABX-49-01). Dr. Ekambaranellore Prakash from Indus Biotech was involved in planning the experimental study. Indus Biotech was involved in the preparation and analysis of the compounds IND02 and IND02-trimer which were isolated, purified and characterized by Dr. Mohan Vishwaraman. The other funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was supported by the Agence Nationale de la Recherche sur le SIDA (ANRS) and B. J.C. was supported by a grant from Sidaction and "la Fondation Pierre Berg?". Sui-Yuan Chang acknowledges the funding from National Science Council (NSC), Taiwan. Soluble CD4 and mAb 17b were obtained through the NIH AIDS Research and Reference Reagent Program from Drs. S. Iyer, J. Robinson and J. Sodroski, respectively. The following HIV-1 strains were obtained through the NIH AIDS Research and Reference Reagent Program from the UNAIDS Network for HIV Isolation and Characterization (92UG029 and 98IN017), Dr. N. Halsey (92HT599), Drs. D. Ellenberger, P. Sullivan and R.B. Lal (96USHIPS4). This work used the platforms of the Grenoble Instruct centre (ISBG;UMS 3518 CNRS-CEA-UJF-EMBL) with support from FRISBI (ANR-10-INSB-05-02) and GRAL (ANR-10-LABX-49-01). We thank Karen Storck and Sylvie Schmidt for technical assistance and DrMelanie Lambotin for fruitful discussions.
PY - 2016/10
Y1 - 2016/10
N2 - Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procyanidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1-7 μM ED50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS) as well as to an antibody (mAb 17b) directed against the gp120 co-receptor binding site with an IC50 in the low μM range. IND02 has thus the remarkable property of simultaneously blocking gp120 binding to its major host cell surface counterparts. Additionally, the IND02-trimer impeded up-regulation of the inhibitory receptors Tim-3 and PD-1 on CD4+ and CD8+ cells, thereby demonstrating its beneficial effect by limiting T cell exhaustion. Among naturally derived products significantly inhibiting HIV-1, the IND02-trimer is the first component demonstrating an entry inhibition property through binding to the viral envelope glycoprotein. These data suggest that cinnamon, a widely consumed spice, could represent a novel and promising candidate for a cost-effective, natural entry inhibitor for HIV-1 which can also down-modulate T cell exhaustion markers Tim-3 and PD-1.
AB - Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procyanidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1-7 μM ED50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS) as well as to an antibody (mAb 17b) directed against the gp120 co-receptor binding site with an IC50 in the low μM range. IND02 has thus the remarkable property of simultaneously blocking gp120 binding to its major host cell surface counterparts. Additionally, the IND02-trimer impeded up-regulation of the inhibitory receptors Tim-3 and PD-1 on CD4+ and CD8+ cells, thereby demonstrating its beneficial effect by limiting T cell exhaustion. Among naturally derived products significantly inhibiting HIV-1, the IND02-trimer is the first component demonstrating an entry inhibition property through binding to the viral envelope glycoprotein. These data suggest that cinnamon, a widely consumed spice, could represent a novel and promising candidate for a cost-effective, natural entry inhibitor for HIV-1 which can also down-modulate T cell exhaustion markers Tim-3 and PD-1.
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U2 - 10.1371/journal.pone.0165386
DO - 10.1371/journal.pone.0165386
M3 - Article
C2 - 27788205
AN - SCOPUS:84992745676
VL - 11
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 10
M1 - e0165386
ER -