Presentation is loading. Please wait.

Presentation is loading. Please wait.

CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 1 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD HIV1- identification of the specific restriction factor.

Similar presentations


Presentation on theme: "CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 1 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD HIV1- identification of the specific restriction factor."— Presentation transcript:

1 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 1 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD HIV1- identification of the specific restriction factor SAMHD1 Monsef Benkirane Institut de Génétique Humaine Montpellier

2 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 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 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 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 SAM HD Putative hydrolase domain Missing in isoform Purification of Vpx-associated proteins

4 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 4 F/H-Vpx: SAMHD1 Tubulin + F/H-Vpx WCE DDB1 - R.S.I SAMHD1 Tubulin DDB1 Mg132 : -+ - VLP-Vpx: ++ - Vpx interacts and induces proteasomal degradation of SAMHD1 SAMHD1 expression correlates with HIV-1 susceptibility shRNAScr(4) Fold increase Vpx/no Vpx N.I. HIV-LUC-G shRNAScr(3)(4) Fold Increase x12 x4 Silencing N.I. HIV-LUC-G

5 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 5 Dynamin-2 siRNA:-ScrDyn2 Actin GFP FSC ScrDyn2SAMHD1-1SAMHD1-2siRNA: N.I. LV GFP 5ng LV GFP 50ng hr 96 hr SAMHD1 DDB1 Tubulin siRNA:-Scr 12 SAMHD1 restricts HIV-1 infection of Dendritic cells Silencing of SAMHD1 in MDDCs Infection of silenced MDDCs with LV-GFP Scr12 HD2 siRNA Fold increase (p24+ cells) Scr12 HD Infection of silenced MDDCs with HIV-G

6 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 6 The big picture Would decreasing Samhd1 levels allow for better immune control of HIV-1 infection?

7 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 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.

8 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 8 Many thanks to: CHABLE-BESSIA Christine SOBHIAN Bijan RINGEARD Mathieu YATIM Ahmad SCHWARTZ Olivier CASARTELLI Nicoletta EMILIANI Stéphane SEGERAL Emmanuel LAGUETTE Nadine


Download ppt "CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD 1 CEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD HIV1- identification of the specific restriction factor."

Similar presentations


Ads by Google