1. Academic Validation
  2. HIV protease inhibitor attenuated astrocyte autophagy involvement in inflammation via p38 MAPK pathway

HIV protease inhibitor attenuated astrocyte autophagy involvement in inflammation via p38 MAPK pathway

  • Antiviral Res. 2022 Nov 10;105463. doi: 10.1016/j.antiviral.2022.105463.
Xue Chen 1 Wei Ding 2 Xiao Cui 3 Jiaqi Wei 1 Yang Zhang 1 Xin Zhang 3 Tong Zhang 4 Yulin Zhang 5
Affiliations

Affiliations

  • 1 Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing Key Laboratory for HIV/AIDS Research, Beijing, 100069, China.
  • 2 Phase Clinical Trial Ward, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
  • 3 Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China.
  • 4 Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing Institute of Hepatology, Beijing Key Laboratory for HIV/AIDS Research, Beijing, 100069, China. Electronic address: zt_doc@ccmu.edu.cn.
  • 5 Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, China. Electronic address: yulinzhang@ccmu.edu.cn.
Abstract

HIV-associated neurocognitive disorder (HAND) is prevalent in people living with HIV, despite the use of antiretroviral therapy (ART). Although several risk factors have been proposed to be related to HAND, substantial effort has been made to explore the neurotoxic effects of ART on HAND. HIV Protease Inhibitor (PI), an essential component of ART, has neurotoxicity in vivo and in vitro, which can contribute to the development of HAND. However, the pathogenesis of PI-associated neurotoxicity remains unclear. Here, we explored whether PI treatment is a potential pathogenic factor for HAND and elucidated its potential mechanisms. In our study, U87 cells were exposed to PIs, including lopinavir (LPV), ritonavir (RTV), darunavir, indinavir, and saquinavir at different concentrations, we found that LPV, LPV/RTV, and saquinavir attenuated Autophagy in U87 cells, the results of Western blot showed that the expression of p62 dramatically was elevated and the level of LC3II/LC3I was decreased. Moreover, comparative transcriptomics revealed the involvement of the inflammatory response in the physiological activities of U87 cells exposed to LPV, with differential genes significantly enriched in the p38 MAPK signaling pathway. In the following study, we verified the results from RNA-sequence using the liquid chip technique, qRT-PCR, Elisa, and western blots, which suggested that LPV induced inflammatory response and the p38 MAPK pathway was involved in this process. Collectively, we demonstrated that PIs attenuated the involvement of astrocyte Autophagy in inflammation via the p38 MAPK pathway, providing new insights into the mechanism of HAND.

Keywords

Astrocytes; Autophagy; HIV protease Inhibitor; HIV-Associated neurocognitive disorder; Inflammation; p38 MAPK signaling Pathway.

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