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www.ias2015.org
HIV-1 Vpu Exploits the Crosstalk Between BST2 and the ILT7 Receptor to Inhibit Innate
Sensing of Infected T cells by pDCs
Mariana G. Bego1, Édouard A. Côté1, Nick Aschman2, Johanne Mercier1, Winfried Weissenhorn2 and Éric A. Cohen1,3
1Institut de Recherches Cliniques de Montréal (IRCM)2 Unit of Virus-Host Interactions, Université Grenoble Alpes
3Department of Microbiology and Immunology, Université de Montréal
Poster : TUPDA0103
BST2/Tetherin: one gene (a few isoforms) and many roles
NF-kB
Sauter, 2010
Vpu
HIV-infected CD4+ T cells are more potent at stimulating pDCs
Most efficient way
pDC sense HIV is via cell
contacts
Iwasaki, A., Immunity , 2012
Sensing and antiviral responses:1- Env-CD4 interaction2- Membrane fusion 3-decapsidation and release of ssRNA into TLR7+ endosome4-triggering of a MyD 88/IRF7 signaling cascade that results in IFN-I and cytokine production
Weak Strong
Goal of the study
To investigate whether HIV exploits
the BST2-ILT7 regulatory axis to
modulate pDC antiviral responses
HIV-1 Vpu suppresses sensing of HIV-1 infected cells by pDCs
Co-culture X4 infected MT4 T cells and PBMCs
Type
I IF
N (
U/m
l)
PBMC + + + + - + - + -Stimuli - TRL7 ago TLR9 ago
Coculture - - - MT4-mock MT4-dU MT4-WT
0
2000
4000
6000
8000
10000
12000
14000
HIV-1 Vpu suppresses sensing of HIV-1 infected cells by pDCs
Co-culture X4 infected MT4 T cells and PBMCs
Type
I IF
N (
U/m
l)
PBMC + + + + - + - + -Stimuli - TRL7 ago TLR9 ago
Coculture - - - MT4-mock MT4-dU MT4-WT
0
2000
4000
6000
8000
10000
12000
14000
Rela
tive
% o
f IFN
rele
ased
dU WT
Mean 52%
***
X4
Mean 57% Mean
46%
* **
ns
Rel
ativ
e %
of
IFN
rel
ease
d
Primary T cells (X4/R5 infection)
dU WT dU WT
X4 R5
Two Working Models
1-In the absence of Vpu, tethered virions are more effectively presented at the cell surface for transmission and sensing by pDCs
2- Vpu modulates the levels of BST2 that can engage and activate ILT7 on pDCs
7
Control of HIV innate sensing by Vpu is BST2-dependent
Rela
tive
% o
f par
ticle
s re
leas
ed
dU WT dU WTMT4-shNT MT4-shBST2
0
20
40
60
80
100
120
38
10090
100
HIV-1 release assay
BST2-depleted MT4 cell lines
Control of HIV innate sensing by Vpu requires the ILT7 pDC inhibitory receptor
A9816412
Non pDCs (PBMCs)pDCs (PBMCs)Enriched pDCsEnriched pDCs siILT7
% M
ax
ILT7-PE
ILT7 depletion in enriched pDCs
B
Soluble ILT7
Interplay between Vpu and BST2
Vpu exploits the crosstalk between BST2 and ILT7 to dampen the antiviral response of PDCs
Through a sophisticated targeted regulation of specific BST2 isoforms, Vpu promotes HIV release while at the same time interfering with pDC antiviral responses through ILT7 activation
This mechanism of innate immune evasion is likely to be important for an efficient early viral dissemination during acute
infection
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Acknowledgements
11
Other Lab Members Fadi Hajjar Johanne Mercier
Collaborators Wei Cao, MD Anderson Cancer Center Yong-Jun Liu, MedImmune Nick Aschman & W. Weissenhorn (Univ.
Grenoble Alpes and UVHCI, UVHCI-CNRS, Grenoble)
Mariana Bego Édouard Bérubé-Côté
Reagents Idera Pharmaceuticals AIDS Reagent Program
The IRCM Clinic staff and healthy volunteers
IRCM Flow Cytometry and Microscopy Cores