Activation of α7 nicotinic acetylcholine receptor promotes HIV-1 transcription
Jing Wen,
Caiqi Zhao,
Jie Chen,
Shuting Song,
Zhekai Lin,
Shitao Xie,
Huaxin Qi,
Jianhua Wang,
Xiao Su
Affiliations
Jing Wen
Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Caiqi Zhao
Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Jie Chen
Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Shuting Song
Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Zhekai Lin
Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Shitao Xie
Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Huaxin Qi
Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China
Jianhua Wang
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510670, China
Xiao Su
Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China; University of Chinese Academy of Sciences, Beijing, 100049, China; Corresponding author. PhD. Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
Alpha7 nicotinic acetylcholine receptor (α7 nAChR), a hub of the cholinergic anti-inflammatory pathway (CAP), is required for the treatment of inflammatory diseases. HIV-1 infection can upregulate the expression of α7 nAChR in T lymphocytes and affect the role of CAP. However, whether α7 nAChR regulates HIV-1 infection in CD4+ T cells is unclear. In this study, we first found that activation of α7 nAChR by GTS-21 (an α7 nAChR agonist) can promote the transcription of HIV-1 proviral DNA. Then, through transcriptome sequencing analysis, we found that p38 MAPK signaling was enriched in GTS-21 treated HIV-latent T cells. Mechanistically, activation of α7 nAChR could increase reactive oxygen species (ROS), reduce DUSP1 and DUSP6, and consequently enhance the phosphorylation of p38 MAPK. By co-immunoprecipitation and liquid chromatography tandem mass spectrometry, we found that p-p38 MAPK interacted with Lamin B1 (LMNB1). Activation of α7 nAChR increased the binding between p-p38 MAPK and LMNB1. We confirmed that knockdown of MAPK14 significantly downregulated NFATC4, a key activator of HIV-1 transcription. Taken together, activation of the α7 nAChR could trigger ROS/p-p38 MAPK/LMNB1/NFATC4 signaling pathway enhancing HIV-1 transcription. We have revealed an unrecognized mechanism of α7 nAChR-mediated neuroimmune regulation of HIV infection.
