Tryptophan Metabolism Activates Aryl Hydrocarbon Receptor-Mediated Pathway To Promote HIV-1 Infection and Reactivation.
Multiple cellular metabolic pathways are altered by HIV-1 infection, with an impact on immune activation, inflammation, and acquisition of non-AIDS comorbid diseases. The dysfunction of tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the underlying mechanism remains unknown. In this study, we demonstrated that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is activated by Trp metabolites to promote HIV-1 infection and reactivation. AHR directly binds to the HIV-1 5' long terminal repeat (5'-LTR) at the molecular level to activate viral transcription and infection, and AHR activation by Trp metabolites increases its nuclear translocation and association with the HIV 5'-LTR; moreover, the binding of AHR with HIV-1 Tat facilitates the recruitment of positive transcription factors to viral promoters. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection.IMPORTANCE Cellular metabolic pathways that are altered by HIV-1 infection may accelerate disease progression. Dysfunction in tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the mechanism responsible was not known. This study demonstrates that Trp metabolites augment the activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, to promote HIV-1 infection and transcription. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection.
['Zhou|Yan-Heng|YH|', 'Sun|Li|L|', 'Chen|Jun|J|', 'Sun|Wei-Wei|WW|', 'Ma|Li|L|', 'Han|Yang|Y|', 'Jin|Xia|X|', 'Zhao|Qing-Xia|QX|', 'Li|Taisheng|T|', 'Lu|Hongzhou|H|', 'Qiu|Xiu|X|', 'Wang|Jian-Hua|JH|']
D023241:Antiretroviral Therapy, Highly Active D018791:CD4 Lymphocyte Count D015967:Gene Expression Regulation, Viral D015658:HIV Infections D016325:HIV Long Terminal Repeat D015497:HIV-1 D054884:Host-Pathogen Interactions D006801:Humans D008954:Models, Biological D018336:Receptors, Aryl Hydrocarbon D015398:Signal Transduction D015533:Transcriptional Activation D014364:Tryptophan D019562:Viral Load D014775:Virus Activation D054322:tat Gene Products, Human Immunodeficiency Virus
HIV-1 aryl hydrocarbon receptor transcription tryptophan metabolite