AHR Signaling In HTLV-1 Pathogenesis

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.Human T-cell leukemia virus type 1(HTLV-1)is a delta-type retrovirus that predominantly infects CD4~+T-cells and etiologically associates with adult T-cell leukemia(ATL)and tropical spastic paraparesis/HTLV-1-associated myelopathy(TSP/HAM).It is generally considered that HTLV-1 is largely latent in vivo because virions and viral proteins were rarely detected in freshly isolated peripheral blood mononuclear cells(PBMCs)of infected individuals.However,the presence of high titles of HTLV-1-specific cytotoxic T-lymphocytes(CTLs)and antibodies in most infected individuals suggests that the immune system is frequently stimulated by newly synthesized HTLV-1 antigens.Thus,HTLV-1 should not be completely silent in vivo,but should somehow reactivate in certain parts of the body rather than peripheral blood.Nevertheless,little is known about where and how HTLV-1 achieves its reactivation so far.Given the critical role of viral gene expression in cell transformation and de novo infection,a better understanding of where and how HTLV-1 achieves its reactivation in vivo can lead to important insights for developing strategies to prevent and treat HTLV-1-associated diseases.Aryl hydrocarbon receptor(AHR)is a ligand-activated transcription factor,which functions in response to heterogenous ligands including xenobiotic substances,dietary components,hememetabolites and tryptophan metabolites.It has been reported that AHR is constitutively overexpressed in HTLV-1-infected T-cell lines as well as primary ATL cells.However,the functional role of AHR in HTLV-1pathogenesis has never been explicated.In this study,we investigate the role of AHR in HTLV-1 pathogenesis and reveal that(i)AHR is a critical regulator of HTLV-1 latency-reactivation-latency switching;(ii)ligand-activated AHR can directly bind to AHR response element(CACGCATAT)located on HTLV-1 long terminal repeat(LTR)and drive HTLV-1 plus-strand transcription;(iii)persistent activation of nuclear factor kappa B(NF-κB)pathway is critical for AHR overexpression in HTLV-1-infected T-cells;(iv)viral protein Tax can elevate AHR expression via activating NF-κB.These evidences suggest that persist NF-κB activation constitutes one key prerequisite for AHR overexpression in infected T-cells,enduing HTLV-1 the capability to switch between latency and reactivation according to the level of AHR ligands in the microenvironment.Accordingly,we propose that HTLV-1 might achieve its reactivation in an AHR-dependent manner in certain parts of the body where are prone to accumulate AHR ligands(possibly bone marrow or gut-associated lymphoid organs/tissues),and address AHR as a potential target for prophylaxis and treatment of HTLV-1-related diseases.