HIV1- identification of the specific restriction factor SAMHD1
8
CEA CHRU CNRS CPU INR A INRI A INSER M INSTITUT PASTEUR IR D 1 CEA CHRU CNRS CPU INR A INRI A INSER M INSTITUT PASTEUR IR D HIV1- identification of the specific restriction factor SAMHD1 Monsef Benkirane Institut de Génétique Humaine Montpellier
-
Upload
alyssa-diaz -
Category
Documents
-
view
55 -
download
2
description
HIV1- identification of the specific restriction factor SAMHD1. Monsef Benkirane Institut de Génétique Humaine Montpellier. Dendritic cells are refractory to HIV-1 infection. X. Does HIV-1 escapes innate immune recognition by avoiding productive infection of Dendritic cells?. - PowerPoint PPT Presentation
Transcript of HIV1- identification of the specific restriction factor SAMHD1
CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
1CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
HIV1- identification of the specific restriction factor
SAMHD1
Monsef BenkiraneInstitut de Génétique Humaine
Montpellier
CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
2
Dendritic cells are refractory to HIV-1 infection
Does HIV-1 escapes innate immune recognition by avoiding productive infection of Dendritic cells?
X
CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
3
> Initially isolated as an IFN-induced factor in macrophages and dendritic cells
> Like for TREX1 and RNASEH2, mutations in SAMHD1
results in Aicardi Goutière Syndrome AGS
AGS is a rare genetic disorder that mimics symptoms from
a congenital infection
AGS is associated with an increased production of IFNα
SAM domain and HD domain 1
Protein-Protein interaction domain
SAMSAM HDHD
Putative hydrolase domain
45 110 164 319 6261
Missing in isoform 2 113-126
Purification of Vpx-associated proteins
CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
4
F/H-Vpx:
SAMHD1
Tubulin
+
F/H-Vpx
WCE
DDB1
-
R.S.I. 1 0.05 0.7
SAMHD1
Tubulin
DDB1
Mg132:
- +-VLP-Vpx:
+ +-
Vpx interacts and induces proteasomal degradation of SAMHD1
SAMHD1 expression correlates with HIV-1 susceptibility
shRNA Scr (4)
Fol
d in
crea
se
Vpx
/no
Vpx
N.I.HIV-LUC-G
shRNA Scr (3) (4)
Fol
d In
crea
se
x12
x4
SilencingN.I.HIV-LUC-G
CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
5
Dynamin-2
siRNA: - Scr Dyn2
Actin
16
4
0.4
62
22
0.1
65
26
0.2
21
4
0.1
GFP
FSC
Scr Dyn2 SAMHD1-1 SAMHD1-2siRNA:
N.I.
LV GFP 5ng
LV GFP 50ng
1 2
48 hr 96 hr
SAMHD1
DDB1
Tubulin
siRNA: - Scr 1 2
SAMHD1 restricts HIV-1 infection of Dendritic cells
Silencing of SAMHD1 in MDDCs
Infection of silenced MDDCs with LV-GFP
Scr 1 2
HD2
siRNAFo
ld in
crea
se
(p24
+ ce
lls)
Scr 1 2
HD4
0
10
20
30
40
Infection of silenced MDDCs with HIV-G
CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
6
The big picture
Would decreasing Samhd1 levels allow for better immune control of HIV-1 infection?
CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
Conclusion and perspectives
7
SAMHD1 is the dendritic and myeloid cells-specific HIV-1-restriction factor counteracted by Vpx
Understanding SAMHD1 function- What is the natural function of SAMHD1 in Macrophages and Dendritic cells?-What substrate for SAMHD1?
Why has HIV-1 not evolved means to counteract SAMHD1?- What is the involvement of SAMHD1 in the physiopathology of AIDS ?
- In non human primates- In HIV elite controllers, LTNPS
Implication for Dendritic cell–based vaccine development.
CEA CHRU
CNRS CPU INRA
INRIA INSERM
INSTITUT PASTEUR
IRD
8
Many thanks to:
CHABLE-BESSIA Christine SOBHIAN Bijan RINGEARD Mathieu YATIM Ahmad SCHWARTZ Olivier
CASARTELLI Nicoletta
EMILIANI StéphaneSEGERAL Emmanuel
LAGUETTE Nadine
