Tryptophan Metabolism Activates Aryl Hydrocarbon Receptor-Mediated Pathway To Promote HIV-1 Infection and Reactivation.

Abstract

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.

• Authors: Yan-Heng Zhou, Li Sun, Jun Chen, Wei-Wei Sun, Li Ma, Yang Han, Xia Jin, Qing-Xia Zhao, Taisheng Li, Hongzhou Lu, Xiu Qiu, Jian-Hua Wang
• Journal: mBio (mBio) Vol. 10 Issue 6 (12 17 2019) ISSN: 2150-7511 [Electronic] United States
• PMID: 31848275 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Zhou et al.

Chemical References

• Receptors, Aryl Hydrocarbon
• tat Gene Products, Human Immunodeficiency Virus
• Tryptophan

Topics

• Antiretroviral Therapy, Highly Active
• CD4 Lymphocyte Count
• Gene Expression Regulation, Viral
• HIV Infections (drug therapy, metabolism, virology)
• HIV Long Terminal Repeat (genetics)
• HIV-1 (physiology)
• Host-Pathogen Interactions
• Humans
• Models, Biological
• Receptors, Aryl Hydrocarbon (metabolism)
• Signal Transduction
• Transcriptional Activation
• Tryptophan (blood, metabolism)
• Viral Load
• Virus Activation
• tat Gene Products, Human Immunodeficiency Virus