Tryptophan Metabolism Activates Aryl Hydrocarbon Receptor-Mediated Pathway To Promote HIV-1 Infection and Reactivation
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
Affiliations
Yan-Heng Zhou
The Joint Center for Infection and Immunity between Guangzhou Institute of Pediatrics, Guangzhou Women and Childrenˋs Medical Center, Guangzhou, China, and Institut Pasteur of Shanghai, Chinese Academy of Sciences (CAS), Shanghai, China
Li Sun
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
Jun Chen
Department of Infections and Immunity, Shanghai Public Health Clinical Center, Shanghai, China
Wei-Wei Sun
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
Li Ma
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
Yang Han
Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
Xia Jin
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
Qing-Xia Zhao
Department of Infection, Zhengzhou Sixth People’s Hospital, Zhengzhou, China
Taisheng Li
Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
Hongzhou Lu
Department of Infections and Immunity, Shanghai Public Health Clinical Center, Shanghai, China
Xiu Qiu
The Joint Center for Infection and Immunity between Guangzhou Institute of Pediatrics, Guangzhou Women and Childrenˋs Medical Center, Guangzhou, China, and Institut Pasteur of Shanghai, Chinese Academy of Sciences (CAS), Shanghai, China
Jian-Hua Wang
CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
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.
