Nuclear import of HIV
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1 Center for Molecular Medicine Nuclear import of HIV Zeger Debyser MD PhD Molecular Virology and Gene Therapy, KULeuven Flanders, Europe
2 HIV/AIDS: in search of novel drugs against new targets High genetic barrier No cross-resistance resistance No (long term) side effects Optimal adherence (QD) Low cost Eradication?
3 The HIV replication cycle
4 Cellular cofactors as novel antiviral targets Inhibitors of viral protein/cofactor interaction Pros Pipeline of novel targets Reduced risk for antiviral resistance (?) Cons Challenge of protein-protein interactions Cellular toxicity (?)
5 Algorithm to identify and validate novel Algorithm to identify and validate novel cofactors as antiviral targets
6 Target identification sirna screen yeast two hybrid co-immunoprecipitation Target validation sirna Transdominant Interaction mutants YES Effect on HIV replication NO Characterization Role in HIV replication Structural biology Cell biology Drug Discovery Rational design Library screening Peptides/mimetics Assay Development In vitro Cell culture Drug Development
7 Target identification sirna screen yeast two hybrid co-immunoprecipitation Target validation sirna Transdominant Interaction mutants LEDGF/p75 TRN-SR2 Snurportin MCM7 VBP-1 BolA YES Effect on HIV replication NO Snurportin VBP-1 MCM7 BolA Characterization Role in HIV replication Structural biology Cell biology Drug Discovery Rational design Library screening Peptides/mimetics Transportin SR2 Assay Development In vitro Cell culture Drug Development LEDGF/p75
8 TRN-SR2 is a co-factor of HIV nuclear import
9 Nuclear import and HIV Introduction Discovery of transportin-sr2 as nuclear import factor of HIV Capsid modulates nuclear import In search of the interaction interface
10 Nucleopore : structure Strambio-De Castillia et al. Nature Reviews Molecular Biology 2010
11 Mechanism of nuclear import Strambio-De Castillia et al. Nature Reviews Molecular Biology 2010
12 Nuclear import and viruses Murine Leukemia Herpes Simplex Baculovirus Parvovirus Virus Influenza A virus Virus Cohen et al., Biochem. Biophys. Acta 2011
13 Nuclear import and HIV Introduction Discovery of transportin-sr2 as nuclear import factor of HIV Capsid modulates nuclear import In search of the interaction interface
14 Transportin-SR2 (TRN-SR2, tnpo3 gene) RanGTP binding RS-protein interaction TRN-SR2 923 aa TRN-SR1 975aa sitrnsr_ bp sitrnsr_ bp TRN-SR2 shuttles essential splicing factors, serine/arginine-rich proteins but also other cargo, between the cytoplasm and the nucleus (Lai et al, JBC, 2000; Lai et al, PNAS, 2001) in a RAN-GTP-dependent way Identified as hit integrase interactor in yeast two hybrid screen in 2003 Christ et al., Curr. Biol. 18, , 2008
15 sitrn-sr2 inhibits HIV-replication NL NL4.3 IIIB ZKNL4.3 ROD RLU RLU simock sitrn-sr_1 sitrn-sr_2 24h sitrn- SR_2MM sigfp sicd4 simock sitrn-sr_1 sitrn-sr_2 72h sitrn- SR_2MM sigfp sicd4 0 simock sitrn-sr_2 sitrn- SR_2MM sicd4 HIV-1 and HIV-2 are inhibited upon TRN-SR2 knockdown. shtrn-sr2 transduced cell lines show a strong block in HIV-1 replication and do not permit viral break through of the virus This block of replication is also observed in human macrophages. Christ et al., Curr. Biol. 18, , 2008
16 Studying nuclear import with GFP-labeled PICs Trans-incorporation Vpr Integrase egfp IN catalytic mutant Integrase deletion proof of integrity of viral particles: immuno staining of MA and CA NERT (natural endogenous reverse transcription) C infection of HeLaP4 cells Analysis of Z-stacks statistical analysis Albanese et al., PLoS One 3(6):e2413, 2008
17 Novel PIC nuclear import assay sitrn-sr2 sitrn-sr2mm Christ et al., Curr. Biol. 18, , 2008
18 TRN-SR2 imports the PIC to the nucleus sitrn-sr2 sitrn-sr2mm cells Novel PIC import assay in living cells using egfp-in virus sitrn-sr2 blocks HIV on its way to the nucleus Christ et al., Curr. Biol. 18, , 2008
19 Discovery of TRN-SR2 as nuclear import factor of HIV Y2H screen (Christ et al., Current biology 2008) Interaction with HIV integrase (reverse Y2H specific for IN) Cofactor of HIV replication HIV-1, HIV-2 not MLV Nuclear import factor (2 LTR, PIC import ) sirna screen (Brass et al., Science 2008) Cofactor of HIV, after RT, before IN HIV-1 not MLV 2 LTR (pers. commun.) CSHL 2011 (bar) sirna screen (König et al Cell 2008) sirna screen (König et al., Cell 2008). Cofactor of HIV replication HIV-1 not MLV
20 Conclusions Depletion of TRN-SR2 in cell culture inhibits HIV-replication to hardly detectable levels PIC PIC TRN-SR2 GTP GDP Ran GDP TRN-SR2 is the nuclear import Cytoplasm factor of the HIV-PIC TRN-SR2 interacts with HIV-IN but not with any other viral protein Nucleus PIC Ran GT P Ran GTP PIC integration
21 Nuclear import and HIV Introduction Discovery of transportin-sr2 as nuclear import factor of HIV Capsid modulates nuclear import In search of the interaction interface
22 Questioning the role of TRN-SR2 IN interaction in nuclear import Capsid is the genetic determinant of HIV dependency on TRN-SR2 (Krishnan et al., J Virol, 2010; Lee et al, Cell Host Microbe, 2010) TRN-SR2 acts (also) on integration and is an export factor of trna (Zhou et al., Plos Pathogens 2011) Role in HIV integration site selection (Ocwieja et al, PLoS Pathog, 2011)
23 Specificity of TRN-SR2 Comparison of retroviral vectors (VSV-G pseudotyped) mock 20 sitr2 0 HIV-1 SIV EIAV FIV MLV simm Not all retroviral vectors are TRN-SR2 dependent Thys et al., Retrovirology 2011
24 HIV-1 N74D CA mutant and TRN-SR2 VSV-G pseudotyped luciferase reporter viruses mock sitr2 simm WT N74D VSV-G pseudotyped HIV-1 N74D CA mutant virus is independent of TRN-SR2 (Lee et al. 2010)
25 HIV-1 N74D CA depends on TRN-SR2 for multiple round replication replication competent virus with HIV wild type envelope Thys et al., Retrovirology 2011
26 Role of viral envelope in TRN-SR2 dependency ph-dependent ph-independent endocytosis (e.g. clathrin) endocytosis (e.g. caveolae) fusion VSV-G Ebola virus MLV HIV measles virus Dimitrov, Nat. Rev. Microbiol., 2004
27 The envelope defines the TRN dependency of the N74D CA mutant % Fluc coun nts/µg prot tein compa ared to mo ock WT N74D WT N74D WT N74D WT N74D WT N74D VSVg Ebo MLV HIV Measl mock TR MM ph dependent endocytosis Caveolar endocytosis Fusion at plasma membrane Thys et al., Retrovirology 2011
28 Conclusions Capsid uncoating is required prior to nuclear import PIC TRN-SR2 Ran GDP Entry and uncoating mechanisms indirectly affect nuclear import Cytoplasm Nucleus PIC GTP GDP Caveat: extrapolation of VSV-G vector data to HIV replication PIC Ran GTP Ran GT P PIC integration
29 Nuclear import and HIV Introduction Discovery of transportin-sr2 as nuclear import factor of HIV Capsid modulates nuclear import In search of the interaction interface
30 Identification of interacting domains Transient overexpression in 293T cells Co-immunoprecipitation
31 Identification of interacting domains kda TRN-SR2 interacts with HIV-1 IN via the IN CCD and CTD
32 Transportin-SR2 pulls down IN but not CA Pulldown Loading control His 6 TRN SR2 GST IN CA BSA TRN SR2 IN CA
33 Characterization of recombinant TRN-SR2 PIC TRN-SR2 Ran GDP PIC GTP GDP Cytoplasm Nucleus PIC Ran GTP Ran GTP PIC integration
34 General conclusions TRN-SR2 is an important cofactor of HIV replication and probably interacts with IN rather than with CA The route of entry affects the nuclear import pathway used by HIV-1 The interaction between IN and TRN-SR2 is RAN-GTP dependent Defined interface at CTD of IN and central domain in TRN-SR2 High impact novel antiviral target
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