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

Cari F. Kessing, Christopher C. Nixon, Chuan Li, Perry Tsai, Hiroshi Takata, Guillaume Mousseau, Phong T. Ho, Jenna B. Honeycutt, Mohammad Fallahi, Lydie Trautmann, J. Victor Garcia, Susana T. Valente

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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. Tat inhibitors are amenable to functional cure approaches, which aim to reduce residual viremia during ART and limit viral rebound during treatment interruption. Using didehydro-Cortistatin A (dCA), Kessing et al. demonstrate the concept in human CD4+ T cells from aviremic individuals and in the bone marrow-liver-thymus mouse model of HIV latency.

Original languageEnglish (US)
Pages (from-to)600-611
Number of pages12
JournalCell Reports
Volume21
Issue number3
DOIs
StatePublished - Oct 17 2017
Externally publishedYes

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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