HIV1- identification of the specific restriction factor SAMHD1 Monsef Benkirane Institut de Génétique Humaine Montpellier ...
Dendritic cells are refractory to HIV-1 infection Does HIV-1 escapes innate immune recognition by avoiding productive infe...
>  Initially isolated as an IFN  -induced factor in macrophages  and dendritic cells > Like for  TREX1  and  RNASEH2,  mu...
Vpx interacts and induces proteasomal degradation of SAMHD1 SAMHD1 expression correlates with HIV-1 susceptibility F/H-Vpx...
SAMHD1 restricts HIV-1 infection of Dendritic cells Silencing of SAMHD1  in MDDCs Infection of silenced MDDCs with LV-GFP ...
The big picture Would decreasing Samhd1 levels allow for better immune control of HIV-1 infection?
Conclusion and perspectives SAMHD1 is the dendritic and myeloid cells-specific HIV-1-restriction factor counteracted by Vp...
Many thanks to: LAGUETTE Nadine CHABLE-BESSIA Christine  SOBHIAN Bijan  RINGEARD Mathieu  YATIM Ahmad  SCHWARTZ Olivier CA...
Upcoming SlideShare
Loading in …5
×

2.2 monsef benkirane

1,053 views
920 views

Published on

Published in: Health & Medicine
0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total views
1,053
On SlideShare
0
From Embeds
0
Number of Embeds
63
Actions
Shares
0
Downloads
15
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide

2.2 monsef benkirane

  1. 1. HIV1- identification of the specific restriction factor SAMHD1 Monsef Benkirane Institut de Génétique Humaine Montpellier CEA CHRU CNRS CPU INRA INRIA INSERM INSTITUT PASTEUR IRD
  2. 2. Dendritic cells are refractory to HIV-1 infection Does HIV-1 escapes innate immune recognition by avoiding productive infection of Dendritic cells? X
  3. 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 IFN α Purification of Vpx-associated proteins SAM domain and HD domain 1 Protein-Protein interaction domain SAM HD Putative hydrolase domain 45 110 164 319 626 1 Missing in isoform 2 113-126
  4. 4. Vpx interacts and induces proteasomal degradation of SAMHD1 SAMHD1 expression correlates with HIV-1 susceptibility F/H-Vpx: SAMHD1 Tubulin + F/H-Vpx WCE DDB1 - R.S.I. 1 0.05 0.7 SAMHD1 Tubulin DDB1 Mg132: - + - VLP-Vpx: + + - shRNA Scr (4) Fold increase Vpx/no Vpx N.I. HIV-LUC-G shRNA Scr (3) (4) Fold Increase x12 x4 Silencing N.I. HIV-LUC-G
  5. 5. SAMHD1 restricts HIV-1 infection of Dendritic cells Silencing of SAMHD1 in MDDCs Infection of silenced MDDCs with LV-GFP Infection of silenced MDDCs with HIV-G 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 SAMHD1-2 siRNA: N.I. LV GFP 5ng LV GFP 50ng 1 2 48 hr 96 hr SAMHD1 DDB1 Tubulin siRNA: - Scr 1 2 Scr 1 2 HD2 siRNA Fold increase (p24+ cells) Scr 1 2 HD4 0 10 20 30 40
  6. 6. The big picture Would decreasing Samhd1 levels allow for better immune control of HIV-1 infection?
  7. 7. Conclusion and perspectives SAMHD1 is the dendritic and myeloid cells-specific HIV-1-restriction factor counteracted by Vpx <ul><li>Understanding SAMHD1 function </li></ul><ul><li>- What is the natural function of SAMHD1 in Macrophages and Dendritic cells? </li></ul><ul><li>What substrate for SAMHD1? </li></ul><ul><li>Why has HIV-1 not evolved means to counteract SAMHD1? </li></ul><ul><li>What is the involvement of SAMHD1 in the physiopathology of AIDS ? </li></ul><ul><ul><li>In non human primates </li></ul></ul><ul><ul><li>In HIV elite controllers, LTNPS </li></ul></ul><ul><li>Implication for Dendritic cell–based vaccine development. </li></ul>
  8. 8. Many thanks to: LAGUETTE Nadine CHABLE-BESSIA Christine SOBHIAN Bijan RINGEARD Mathieu YATIM Ahmad SCHWARTZ Olivier CASARTELLI Nicoletta EMILIANI Stéphane SEGERAL Emmanuel

×