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Cell Rep. 2017 Oct 17;21(3):600-611. doi: 10.1016/j.celrep.2017.09.080.

In Vivo Suppression of HIV Rebound by Didehydro-Cortistatin A, a "Block-and-Lock" Strategy for HIV-1 Treatment.

Author information

1
Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA.
2
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, NC, USA.
3
U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.
4
Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, NC, USA. Electronic address: victor_garcia@med.unc.edu.
5
Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA. Electronic address: svalente@scripps.edu.

Abstract

HIV-1 Tat activates viral transcription and limited Tat transactivation correlates with latency establishment. We postulated a "block-and-lock" functional cure approach based on properties of the Tat inhibitor didehydro-Cortistatin A (dCA). HIV-1 transcriptional inhibitors could block ongoing viremia during antiretroviral therapy (ART), locking the HIV promoter in persistent latency. We investigated this hypothesis in human CD4+ T cells isolated from aviremic individuals. Combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound after treatment interruption, even during strong cellular activation. We show that dCA mediates epigenetic silencing by increasing nucleosomal occupancy at Nucleosome-1, restricting RNAPII recruitment to the HIV-1 promoter. The efficacy of dCA was studied in the bone marrow-liver-thymus (BLT) mouse model of HIV latency and persistence. Adding dCA to ART-suppressed mice systemically reduces viral mRNA in tissues. Moreover, dCA significantly delays and reduces viral rebound levels upon treatment interruption. Altogether, this work demonstrates the potential of block-and-lock cure strategies.

KEYWORDS:

HIV latency; HIV-1; HIV-1 transcription; Tat inhibitor; block-and-lock; didehydro-Cortistatin A; epigenetics; humanized mouse model; infected CD4+T cells; latent reservoir

PMID:
29045830
PMCID:
PMC5653276
DOI:
10.1016/j.celrep.2017.09.080
[Indexed for MEDLINE]
Free PMC Article

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