posted on 2020-05-30, 12:03authored byAnne-Marie
W. Turner, Raghuvar Dronamraju, Frances Potjewyd, Katherine S. James, Daniel K. Winecoff, Jennifer L. Kirchherr, Nancie M. Archin, Edward P. Browne, Brian D. Strahl, David M. Margolis, Lindsey I. James
A hallmark of human
immunodeficiency type-1 (HIV) infection is
the integration of the viral genome into host chromatin, resulting
in a latent reservoir that persists despite antiviral therapy or immune
response. Thus, key priorities toward eradication of HIV infection
are to understand the mechanisms that allow HIV latency and to develop
latency reversal agents (LRAs) that can facilitate the clearance of
latently infected cells. The repressive H3K27me3 histone mark, catalyzed
by the PRC2 complex, plays a pivotal role in transcriptional repression
at the viral promoter in both cell line and primary CD4+ T cell models
of latency. EZH2 inhibitors which block H3K27 methylation have been
shown to act as LRAs, suggesting other PRC2 components could also
be potential targets for latency reversal. EED, a core component of
PRC2, ensures the propagation of H3K27me3 by allosterically activating
EZH2 methyltransferase activity. Therefore, we sought to investigate
if inhibition of EED would also reverse latency. Inhibitors of EED,
EED226 and A-395, demonstrated latency reversal activity as single
agents, and this activity was further enhanced when used in combination
with other known LRAs. Loss of H3K27me3 following EED inhibition significantly
increased the levels of H3K27 acetylation globally and at the HIV
LTR. These results further confirm that PRC2 mediated repression plays
a significant role in the maintenance of HIV latency and suggest that
EED may serve as a promising new target for LRA development.