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Regulation of HIV transcription and mechanisims of latency. viral – host interactions.

Lost in transcription – mechanisms that drive HIV latency. Ongoing Projects. Regulation of HIV transcription and mechanisims of latency. viral – host interactions. Use of lentiviruses for targeting specific cells for gene therpy application.

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Regulation of HIV transcription and mechanisims of latency. viral – host interactions.

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  1. Lost in transcription – mechanisms that drive HIV latency Ongoing Projects Regulation of HIV transcription and mechanisims of latency. viral – host interactions. Use of lentiviruses for targeting specific cells for gene therpy application. Dan Levy - Role of SETD6 in modulating HIV latency. Alon Freidman – Targeting of lentiviruses to specific cells. Ongoing Collaborations

  2. The Problem - latency is a block for HIV eradication Total: 34.2 million People HIV infected Latent HIV reservoirs that are refractory to therapy New HIV infections People AIDS- related deaths HAART Latency- a reversibly low-productive state of infection, where infected cells retain the capacity to fully re-emerge and produce de-novo viral particles

  3. What are the molecular mechanisms that regulate HIV latency ? Regulation of HIV transcriptional activation HYPOTHESIS Role of Positive transcription elongation b -PTEFb Ways to reactivate latent HIV and eliminate viral reservoirs with HAART ?

  4. Latency corresponds with transcription activation and chromatin state gag A Active State Ac Ac Ac Ac NF-kB Open chromatin SWI/SNF remodeling HIV Provirus rev 5’LTR 3’LTR vif tat env pol nef vpr vpu B HKMT/ SUV39H1 G9a NF-AT Latent State NF-AT HIV provirus CCR5/CXCR4 CD4 Condensed chromatin TAFs… TAFs… P-TEFb HATs HDACs PRC1/2 Remodeling EZH2 NF-kB YY1/LSF CBF-1 AP4 met H3K27 me3 met met met H3K9 me2 CpG islands nuc1

  5. HIV Tat - a master switch of viral transcription P-TEFb Cyclin T1 CDK9 P P P P LTR TAR HIV Tat RNA Polymerase II

  6. Recruitment modes of P-TEFb to the viral promoter Tat independent (basal) Tat dependent I II III SEC Brd4 P P P P P P P P SEC P P SEC ELL2 AFF4 TAR AFF4 ENL/ AF9 ENL/ AF9 CycT1 Cdk9 AFF4 CycT1 Ac P A ENL/ AF9 Tat Cdk9 ELL2 ELL2 CycT1 Cdk9 YEATS motif PAFc NF-kB NELF A-D P RelA/ p50 E TATA Ac Ac A A mediator RNAPII RNAPII TAR LTR TAR NFkB Sp1 P DSIF/ spt5 CTD Cdk9 PID YSPTSPS CycT1 HIV LTR

  7. P-TEFb equilibrium in cells modulates HIV latency Cdk9 HEXIM1 P13K/ Akt HEXIM1 CycT1 • PKC activators (Bryostatin, Prostratin) • HDAC inhibitors (SAHA) • Bromodomain and extra-terminal (BET) bromodomain inhibitors (JQ1, I-BET) • Hypertrophic or stress signals (UV), TCR ligation (IL-2/CD3 Ab) • HIV infection Tat LARP7 T270 S278 MePCE P P P P P 5’ Brd4 7SK snRNA Ub T186 3’ Cdk9 Cdk9 Ac CycT1 CycT1 K380;386;390;404 Resting stat - inactive P-TEFb Active state - free active P-TEFb

  8. What are the molecular mechanisms that regulate HIV latency ? Regulation of Transcriptional activation Ways to reactivate latent HIV and eliminate viral reservoirs ? Role of P-TEFb in establishment of HIV latency 1 2 Mechanisms that promote viral gene activation Role of chromatin modulation (collaboration of D.Levy) 3 Modes of recruitment of P-TEFb to the viral promoter. Screen for small molecules that can reactivate latent HIV identification of host factors that modulate HIV latency 4

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