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

Abstract

SUMMARY 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 increased 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.

Precision mouse models with expanded tropism for human pathogens

“…To extend the breadth of human pathogens that can be studied using humanized mice, we validated two models, LoM and BLT-L mice, which provide human lung tissue as an in vivo target for human pathogens either without (LoM) or with (BLT-L mice) an autologous systemic human immune system. The engraftment levels of human immune cell types in BLT-L mice are similar to previously reported BLT mice [55][56][57] . The subcutaneously implanted human lung tissue expands and develops into lung implants containing human epithelial, endothelial and mesenchymal cells and a vasculature of human origin.…”

The Tat inhibitor didehydro‐cortistatin A suppresses SIV replication and reactivation

“…The nucleosome 1 (Nuc-1) downstream from the transcription starting site directly impedes transcription from the HIV-1 promoter (13,16,17). Over time, inhibition of Tat-dependent HIV-1 transcription by dCA results in the accumulation of epigenetic modifications that lead to increased occupancy of Nuc-1, restricting RNAPII recruitment and elongation (20). As such, dCA prompts the viral promoter into deep transcriptional inhibition, refractory to viral reactivation by the standard panel of activators, such as cytokines, HDAC inhibitors, and protein kinase C (PKC) activators (21).…”

“…As such, dCA prompts the viral promoter into deep transcriptional inhibition, refractory to viral reactivation by the standard panel of activators, such as cytokines, HDAC inhibitors, and protein kinase C (PKC) activators (21). Discontinuation of dCA treatment of infected CD4 + T cells does not result in immediate viral rebound, as the chromatin environment of the HIV promoter is epigenetically repressed (19)(20)(21). Importantly, in human CD4 + T cells isolated from aviremic individuals, combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound during treatment interruption (20).…”

“…Discontinuation of dCA treatment of infected CD4 + T cells does not result in immediate viral rebound, as the chromatin environment of the HIV promoter is epigenetically repressed (19)(20)(21). Importantly, in human CD4 + T cells isolated from aviremic individuals, combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound during treatment interruption (20). Furthermore, in the bone marrow-liverthymus mouse model of HIV latency and persistence, adding dCA to ART-suppressed mice reduces viral RNA in tissues and significantly delays and diminishes viral rebound upon treatment interruption (20,21).…”

Towards a cure for human immunodeficiency virus

“…This has been termed ‘block and lock’. Didehydro‐cortistatin A, a novel drug derived from a marine sponge, can induce a state of deep latency through changes in DNA structure both in vitro and in the humanised mouse model, delaying viral rebound off ART, but clinical trials in humans have not yet begun . Gene therapy approaches could also be used to silence permanently HIV RNA using small interfering RNA (siRNA) …”