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HIV1- identification of the specific restriction factor SAMHD1

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?.

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HIV1- identification of the specific restriction factor SAMHD1

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

  2. Dendriticcells 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 1 45 110 164 319 626 SAM HD Protein-Protein interaction domain Putative hydrolase domain Missing in isoform 2 113-126 > Initially isolated as an IFN-induced factor in macrophages and dendritic cells > Like for TREX1 and RNASEH2, mutations in SAMHD1 results in AicardiGoutière Syndrome AGS AGS is a rare genetic disorder that mimics symptoms from a congenital infection AGS isassociatedwith an increased production of IFNα

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

  5. 0.1 0.4 0.2 0.1 4 4 26 22 21 16 65 62 siRNA: - Scr Dyn2 Dynamin-2 siRNA: Scr Dyn2 SAMHD1-1 SAMHD1-2 Actin 48 hr 96 hr 1 2 1 2 siRNA: - Scr GFP N.I. SAMHD1 DDB1 Tubulin LV GFP 5ng LV GFP 50ng FSC SAMHD1 restricts HIV-1 infection of Dendritic cells Silencing of SAMHD1 in MDDCs 40 30 Fold increase (p24+ cells) 20 Infection of silenced MDDCs with LV-GFP 10 0 siRNA Scr 1 2 Scr 1 2 HD4 HD2 Infection of silenced MDDCs with HIV-G

  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: SCHWARTZ Olivier CASARTELLI Nicoletta LAGUETTE Nadine CHABLE-BESSIA Christine SOBHIAN Bijan RINGEARD Mathieu YATIM Ahmad EMILIANI Stéphane SEGERAL Emmanuel

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