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

Date Published: March 20, 2014

Publisher: Public Library of Science

Author(s): Zachary Klase, Venkat S. R. K. Yedavalli, Laurent Houzet, Molly Perkins, Frank Maldarelli, Jason Brenchley, Klaus Strebel, Paul Liu, Kuan-Teh Jeang, Jeremy Luban.


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.

Partial Text

Human Immunodeficiency Virus type I (HIV-1) is the etiologic agent of Acquired Immunodeficiency Syndrome (AIDS). HIV-1 has a complex life cycle that in part involves a unique transcriptional interaction between the viral Tat protein and its target RNA element (TAR) found in the R sequence of the LTR [1]–[3]. In the absence of treatment, most HIV-1 infected individuals will experience a steady decline in the number of CD4+ T-cells, progress to AIDS and eventually die as the result of acquiring opportunistic infections.

In this study, we report a role for the RUNX family of transcription factors in repressing HIV-1 transcription driven by the viral LTR. The RUNX1 protein is involved in fate determination of T-cells and control of CD4 expression [12], [14], [38], [39] making its potential involvement in HIV replication of physiological interest. We have identified interaction of RUNX1 and the co-factor CBF-β with the viral LTR through a potential binding site (Fig 3) and that alteration of RUNX1 and CBF-β expression alters viral replication (Fig 1).




0 0 vote
Article Rating
Notify of
Inline Feedbacks
View all comments