Presentation on theme: "HIV1- identification of the specific restriction factor SAMHD1"— Presentation transcript:
1 HIV1- identification of the specific restriction factor SAMHD1 Monsef BenkiraneInstitut de Génétique HumaineMontpellierCEACHRUCNRSCPUINRAINRIAINSERMINSTITUT PASTEURIRD
2 Dendritic cells are refractory to HIV-1 infection XDoes HIV-1 escapes innate immune recognition by avoiding productive infection of Dendritic cells?
3 Purification of Vpx-associated proteins SAM domain and HD domain 1Protein-Protein interaction domainSAMHDPutative hydrolase domain451101643196261Missing in isoform> Initially isolated as an IFN-induced factor in macrophagesand dendritic cells> Like for TREX1 and RNASEH2, mutations in SAMHD1results in Aicardi Goutière Syndrome AGSAGS is a rare genetic disorder that mimics symptoms froma congenital infectionAGS is associated with an increased production of IFNα
4 Vpx interacts and induces proteasomal degradation of SAMHD1 F/H-Vpx:SAMHD1Tubulin+F/H-VpxWCEDDB1-R.S.I.10.050.7SAMHD1TubulinDDB1Mg132:-+VLP-Vpx:SAMHD1 expression correlates with HIV-1 susceptibilityshRNAScr(3)(4)Fold Increasex12x4SilencingN.I.HIV-LUC-GshRNAScr(4)Fold increaseVpx/no VpxN.I.HIV-LUC-G
5 SAMHD1 restricts HIV-1 infection of Dendritic cells Silencing of SAMHD1in MDDCs1248 hr96 hrSAMHD1DDB1TubulinsiRNA:-ScrDynamin-2siRNA:-ScrDyn2ActinInfection of silenced MDDCs with LV-GFP1640.462220.165260.221GFPFSCScrDyn2SAMHD1-1SAMHD1-2siRNA:N.I.LV GFP5ng50ngInfection of silenced MDDCs with HIV-GScr12HD2siRNAFold increase(p24+ cells)HD410203040
6 The big pictureWould 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 VpxUnderstanding 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 primatesIn HIV elite controllers, LTNPSImplication for Dendritic cell–based vaccine development.