AHR is a tunable knob that controls HTLV-1 latency-reactivation switching

Abstract

Establishing latent infection but retaining the capability to reactivate in certain circumstance is an ingenious tactic for retroviruses to persist in vivo while evading host immune surveillance. Many evidences indicate that Human T-cell leukemia virus type 1 (HTLV-1) is not completely silent in vivo . However, signals that trigger HTLV-1 latency-reactivation switching remain poorly understood. Here, we show that aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, plays a critical role in HTLV-1 plus-strand expression. Importantly, HTLV-1 reactivation could be tunably manipulated by modulating the level of AHR ligands. Mechanistically, activated AHR binds to HTLV-1 LTR dioxin response element (DRE) site (CACGCATAT) and drives plus-strand transcription. On the other hand, persistent activation of nuclear factor kappa B (NF-κB) pathway constitutes one key prerequisite for AHR overexpression in HTLV-1 infected T-cells, setting the stage for the advent of AHR signaling. Our findings suggest that HTLV-1 might achieve its reactivation in vivo when encountering environmental, dietary, microbial and metabolic cues that induce sufficient AHR signaling.

Targeting Aryl Hydrocarbon Receptor Signaling Enhances Type I Interferon-Independent Resistance to Herpes Simplex Virus

“…Our study uncovers that an interruption of the AHR pathway results in enhanced antiviral resistance in a type I IFN-independent manner. These findings are consistent with recent studies demonstrating that AHR signaling can promote infections by several viruses, including HSV-1 ( 15 , 18 , 22 , 25 ). Strikingly, novel research showed that an AHR inhibitor not only eliminates detrimental damage in respiratory function caused by IFN-β or IFN-γ but also ameliorates lung pathology caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in hACE2-transgenic mice ( 33 ).…”

“…It also has been reported that HIV-1 infection and reactivation are positively correlated with AHR activation ( 24 ). The binding of activated AHR to the human T-cell lymphotropic virus type 1 (HTLV-1) long terminal repeat (LTR) dioxin response element (DRE) site has been shown to drive HTLV-1 plus-strand transcription, which is critical for viral reactivation and replication ( 25 ). Human CMV (HCMV) infection led to elevated levels of kynurenine, which is an endogenous AHR ligand, and knockdown or inhibition of AHR with chemicals decreased viral RNA levels and ameliorated RNA expression, which are associated with the cell cycle and blocked in CMV infection ( 26 ).…”

Time-course of host cell transcription during the HTLV-1 transcriptional burst

“…The factors that regulate the spontaneous onset of expression of the provirus are not fully understood, but include the proviral integration site [58], cell stress [20, 59], AHR signaling [60], and ubiquitinylation of histone 2A lysine 119 by polycomb repressive complex 1 (PRC1) [61]. RING1 , RYBP and KDM2B are members of the non-canonical PRC1 (ncPRC1) [62] and their expression was up-regulated during the burst (Fig 7).…”

Novel Ferrocene Derivatives Induce Apoptosis through Mitochondria-Dependent and Cell Cycle Arrest via PI3K/Akt/mTOR Signaling Pathway in T Cell Acute Lymphoblastic Leukemia

“…Recently, great progress has been made in this field. We found that the aryl hydrocarbon receptor (AHR) was a tunable knob and controlled HTLV-1 latency-reactivation switching [ 3 ], and the activation of Notch1 signaling by HTLV-1 Tax promoted proliferation of adult T cell leukemia cells [ 4 ]. T cell acute lymphoblastic leukemia (T-ALL), a malignant hematologic disease characterized by the uncontrolled proliferation of immature T-lymphoid cells, is more frequently reported in pediatric patients and hard to cure [ 5 ].…”