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

Author summary HTLV-1 is considered largely latentin vivobecause viral products were rarely detected in freshly isolated PBMCs of infected individuals. However, the existence of strong HTLV-1-specific immune response in most infected individuals suggests that the virus should not be completely silentin vivo. Since viral gene expression plays a critical role in cell transformation andde novoinfection, a novel insight into where and how HTLV-1 achieves its reactivationin vivois essential for developing new therapeutic approaches. AHR is a ligand-activated transcription factor that regulates intricate transcriptional programs in response to environmental, dietary, microbial and metabolic cues. It has been reported that AHR is constitutively overexpressed in HTLV-1-infected T-cells. Nevertheless, the functional role of AHR in HTLV-1 pathogenesis is still obscure. In this study, we show that activated AHR can directly bind to HTLV-1 LTR DRE site (CACGCATAT) and drive HTLV-1 plus-strand transcription. Importantly, HTLV-1 latency-reactivation-latency switching could be manipulated in MT-1 cells by adding and removing additional kynurenine (a well-known AHR ligand). Moreover, we explicate that the persistent NF-kappa B activation is critical for AHR overexpression in HTLV-1-infected T-cells. These results imply that constitutive AHR overexpression in infected T-cells endues HTLV-1 the potential to reactivate from latency when the level of AHR ligands reaches a certain threshold. Accordingly, we propose that HTLV-1 might achieve its reactivation in certain parts of the body that are prone to accumulate AHR ligands. Establishing latent infection but retaining the capability to reactivate in certain circumstance is an ingenious tactic for retroviruses to persistin vivowhile evading host immune surveillance. Many evidences indicate that Human T-cell leukemia virus type 1 (HTLV-1) is not completely silentin 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-kappa B) 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 reactivationin vivowhen encountering environmental, dietary, microbial and metabolic cues that induce sufficient AHR signaling.