NEW YORK (Reuters Health) – The short isoform of the BET protein BRD4 promotes HIV-1 latency, which can be overcome by treatment with one of the new chemotherapeutic BET protein inhibitors, researchers report.
“BET inhibitors are potent reactivators of latent HIV and could serve as part of a future ‘show and kill’ clinical strategy,” Dr. Melanie Ott from University of California, San Francisco, told Reuters Health by email. “BET inhibitor treatment could lead to significant reactivation of endogenous retroelements and retroviruses, a process that should be monitored also in current early phase clinical trial testing BET inhibitors in conditions like cancer.”
Bromodomain and extraterminal domain (BET) proteins commonly activate cellular gene expression, but inhibiting their recruitment reactivates latent HIV-1 transcription.
Dr. Ott and colleagues investigated the functional contributions of the long (BRD4L) and short (BRD4S) isoforms of BRD protein to the enforcement of HIV-1 latency.
BRD4S emerged as a corepressor of HIV-1 transcription and a relevant target of the BET inhibitor JQ1, which affected T-cell reactivation in the presence of BRD4S, less so in the presence of BRD4L, and not at all in their absence.
BRD4S was enriched in the chromatin fraction of latently infected T cells, and cytoplasmic levels of both BRD4 isoforms increased significantly in the presence of JQ1, according to the August 24 Molecular Cell online report.
JQ1 exposure led to reversal of HIV-1 latency by way of marked nucleosome remodeling at the latent HIV-1 promoter, which was dependent on the activity of BRG1-associated factors (BAFs), an SWI/SNF chromatin-remodeling complex with known repressive functions in HIV-1 transcription.
BRD4S directly bound BRG1, a catalytic subunit of BAF, via its bromodomain and extraterminal (ET) domain, and it was necessary for BRG1 recruitment to the latent HIV-1 promoter.
The researchers propose that JQ1-mediated release of BRD4S-BRG1 is a critical early derepressive step required to overcome HIV-1 latency.
“Multiple clinical trials with various BET inhibitors are currently in early stages specifically for applications in cancer,” they note. “In addition, combinatorial treatment with BET inhibitors and low-dose protein kinase C agonists is currently the most effective way to reactivate latent HIV from CD4+ T cells isolated from aviremic HIV+ individuals, rendering BET inhibitors attractive candidates in future clinical trials targeting HIV-1 latency.”
“We anticipate that our data in the context of previous literature will inform future studies into the pleiotropic functions of this epigenetic regulator, not only in HIV biology but also in various noninfectious pathological conditions,” the researchers conclude.
“HIV latency is complex, and important molecular mechanisms are still to be discovered that will inform clinical trials in the future,” Dr. Ott said.
Dr. Jian Zhu from the University of Rochester’s Center for AIDS Research, Rochester, New York, told Reuters Health by email, “The most interesting finding of this paper is that they identified a short version of BRD4 that may execute the suppressive function to maintain the silence of latent HIV.”
“To eliminate the HIV latent reservoirs, a BET inhibitor like JQ1 could be a useful latency-reversing agent that would initially ‘shock and kill’ those ‘reactivatable’ HIV proviruses, followed by the administration of other latency-reinforcing agents to permanently silence the rest of the latent HIV,” he suggested.
Dr. Zhu added, “Although JQ1 targets BRD4, its indirect effect is to remove the suppressive BRG1-associated factors (BAFs), an SWI/SNF chromatin-remodeling complex, from latent HIV promoter. It is also an interesting discovery. Therefore, theoretically the BRG1 ATPase could be a new target for development of its small-molecule inhibitors to eliminate latent HIV.”
SOURCE: http://bit.ly/2wiyk0F
Mol Cell 2017.
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