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HIV1- identification of the specific restriction factor SAMHD1

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Presentation on theme: "HIV1- identification of the specific restriction factor SAMHD1"— Presentation transcript:

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 Dendritic cells are refractory to HIV-1 infection
X Does HIV-1 escapes innate immune recognition by avoiding productive infection of Dendritic cells?

3 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 > 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

4 Vpx interacts and induces proteasomal degradation of SAMHD1
F/H-Vpx: SAMHD1 Tubulin + F/H-Vpx WCE DDB1 - R.S.I. 1 0.05 0.7 SAMHD1 Tubulin DDB1 Mg132: - + VLP-Vpx: SAMHD1 expression correlates with HIV-1 susceptibility shRNA Scr (3) (4) Fold Increase x12 x4 Silencing N.I. HIV-LUC-G shRNA Scr (4) Fold increase Vpx/no Vpx N.I. HIV-LUC-G

5 SAMHD1 restricts HIV-1 infection of Dendritic cells
Silencing of SAMHD1 in MDDCs 1 2 48 hr 96 hr SAMHD1 DDB1 Tubulin siRNA: - Scr Dynamin-2 siRNA: - Scr Dyn2 Actin Infection of silenced MDDCs with LV-GFP 16 4 0.4 62 22 0.1 65 26 0.2 21 GFP FSC Scr Dyn2 SAMHD1-1 SAMHD1-2 siRNA: N.I. LV GFP 5ng 50ng Infection of silenced MDDCs with HIV-G Scr 1 2 HD2 siRNA Fold increase (p24+ cells) HD4 10 20 30 40

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

7 Conclusion and perspectives
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 Many thanks to: CHABLE-BESSIA Christine SOBHIAN Bijan RINGEARD Mathieu YATIM Ahmad LAGUETTE Nadine EMILIANI Stéphane SEGERAL Emmanuel SCHWARTZ Olivier CASARTELLI Nicoletta

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