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

doi:10.1016/j.cellin.2022.100028

Activation of α7 nicotinic acetylcholine receptor promotes HIV-1 transcription

Cell Insight. 2022 Apr 27;1(3):100028. doi: 10.1016/j.cellin.2022.100028. eCollection 2022 Jun.

Authors

Jing Wen^{1

2

3}, Caiqi Zhao^{1

2

3}, Jie Chen^{1

2

3}, Shuting Song^{1

2

3}, Zhekai Lin^{1

2

3}, Shitao Xie^{1

2

3}, Huaxin Qi^{1

2

3}, Jianhua Wang⁴, Xiao Su^{1

2

3}

Affiliations

¹ Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
² CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
³ University of Chinese Academy of Sciences, Beijing, 100049, China.
⁴ Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510670, China.

Abstract

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.

Keywords: HIV-1; LMNB1; ROS; p38 MAPK; α7 nAChR.