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PLoS One. 2016 Mar 2;11(3):e0150037. doi: 10.1371/journal.pone.0150037. eCollection 2016.

Reactivation of Latent HIV-1 Expression by Engineered TALE Transcription Factors.

Author information

1
Research Institute for Medicines (iMed ULisboa), Faculdadede Farmácia, Universidade de Lisboa, Lisboa, Portugal.
2
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, United States of America.
3
Departments of Chemistry, The Scripps Research Institute, La Jolla, California, United States of America.
4
Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, United States of America.

Abstract

The presence of replication-competent HIV-1 -which resides mainly in resting CD4+ T cells--is a major hurdle to its eradication. While pharmacological approaches have been useful for inducing the expression of this latent population of virus, they have been unable to purge HIV-1 from all its reservoirs. Additionally, many of these strategies have been associated with adverse effects, underscoring the need for alternative approaches capable of reactivating viral expression. Here we show that engineered transcriptional modulators based on customizable transcription activator-like effector (TALE) proteins can induce gene expression from the HIV-1 long terminal repeat promoter, and that combinations of TALE transcription factors can synergistically reactivate latent viral expression in cell line models of HIV-1 latency. We further show that complementing TALE transcription factors with Vorinostat, a histone deacetylase inhibitor, enhances HIV-1 expression in latency models. Collectively, these findings demonstrate that TALE transcription factors are a potentially effective alternative to current pharmacological routes for reactivating latent virus and that combining synthetic transcriptional activators with histone deacetylase inhibitors could lead to the development of improved therapies for latent HIV-1 infection.

PMID:
26933881
PMCID:
PMC4774903
DOI:
10.1371/journal.pone.0150037
[Indexed for MEDLINE]
Free PMC Article

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