1 / 8

Mechanisms and Regulation of HIV Latency: Targeting Viral Reservoirs for Eradication

This ongoing project aims to understand the molecular mechanisms that drive HIV latency and explore strategies to reactivate latent HIV and eliminate viral reservoirs. The research includes investigating the role of positive transcription elongation factor b (P-TEFb) in establishing HIV latency, exploring chromatin modulation, and identifying small molecules and host factors for reactivation.

jgreenfield
Download Presentation

Mechanisms and Regulation of HIV Latency: Targeting Viral Reservoirs for Eradication

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related