Activation of HIV-1 from Latent Infection via Synergy of RUNX1 Inhibitor Ro5-3335 and SAHA

PLoS Pathogens

Paul Liu¹  Frank Maldarelli²  Venkat S. R. K. Yedavalli³  Laurent Houzet³  Zachary Klase³  Jason Brenchley³  Kuan-Teh Jeang³  Molly Perkins³  Klaus Strebel³ 

[1] Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America;Host Virus Interaction Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America;Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: HIV-1;    T cells;    Transfection;    Small interfering RNAs;    RNA extraction;    HIV;    293T cells;    Viral replication;   

DOI  :  10.1371/journal.ppat.1003997

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY