Journal article
Activation of HIV-1 from latent infection via synergy of RUNX1 inhibitor Ro5-3335 and SAHA
PLoS pathogens, v 10(3), e1003997
01 Mar 2014
PMID: 24651404
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
A major barrier to the elimination of HIV-1 infection is the presence of a pool of long-lived, latently infected CD4+ memory T-cells. The search for treatments to re-activate latent HIV to aid in clearance is hindered by the incomplete understanding of the mechanisms that lead to transcriptional silencing of viral gene expression in host cells. Here we identify a previously unknown role for RUNX1 in HIV-1 transcriptional latency. The RUNX proteins, in combination with the co-factor CBF-β, are critical transcriptional regulators in T-cells. RUNX1 strongly modulates CD4 expression and contributes to CD4+ T-cell function. We show that RUNX1 can bind DNA sequences within the HIV-1 LTR and that this binding represses transcription. Using patient samples we show a negative correlation between RUNX1 expression and viral load. Furthermore, we find that pharmacologic inhibition of RUNX1 by a small molecule inhibitor, Ro5-3335, synergizes with the histone deacetylase (HDAC) inhibitor SAHA (Vorinostat) to enhance the activation of latent HIV-1 in both cell lines and PBMCs from patients. Our findings indicate that RUNX1 and CBF-β cooperate in cells to modulate HIV-1 replication, identifying for the first time RUNX1 as a cellular factor involved in HIV-1 latency. This work highlights the therapeutic potential of inhibitors of RUNX1 to re-activate virus and aid in clearance of HIV-1.
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Details
- Title
- Activation of HIV-1 from latent infection via synergy of RUNX1 inhibitor Ro5-3335 and SAHA
- Creators
- Zachary Klase - National Institute of Allergy and Infectious DiseasesVenkat S R K Yedavalli - National Institute of Allergy and Infectious DiseasesLaurent Houzet - National Institute of Allergy and Infectious DiseasesMolly Perkins - National Institutes of HealthFrank Maldarelli - National Institutes of HealthJason Brenchley - National Institutes of HealthKlaus Strebel - National Institute of Allergy and Infectious DiseasesPaul Liu - National Human Genome Research InstituteKuan-Teh Jeang - National Institute of Allergy and Infectious Diseases
- Publication Details
- PLoS pathogens, v 10(3), e1003997
- Publisher
- Public LIbrary of Science (PLOS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000337470300040
- Scopus ID
- 2-s2.0-84897394404
- Other Identifier
- 991021902597204721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Microbiology
- Parasitology
- Virology