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

Cell Reports

Guillaume Mousseau¹  Susana T. Valente¹  Chuan Li¹  Cari F. Kessing¹  Mohammad Fallahi¹  Jenna B. Honeycutt²  Phong T. Ho²  Perry Tsai²  J. Victor Garcia²  Christopher C. Nixon²  Lydie Trautmann³  Hiroshi Takata³ 

[1] Department of Immunology and Microbiology, The Scripps Research Institute, Jupiter, FL, USA;Division of Infectious Diseases, Center for AIDS Research, University of North Carolina, School of Medicine, Chapel Hill, NC, USA;U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA;

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

DOI  :  10.1016/j.celrep.2017.09.080

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown