Lovastatin Inhibits HIV-1-Induced MHC-I Downregulation by Targeting Nef–AP-1 Complex Formation: A New Strategy to Boost Immune Eradication of HIV-1 Infected Cells

Frontiers in Immunology

Bingfeng Liu¹  Linghua Li¹  Weiping Cai¹  Xiaoping Tang¹  Qifei Hu²  Hui Zhang²  Fan Zou³  Xiancai Ma⁴  Lijuan Lu⁴  Kai Deng⁴  Baijin Xia⁴  Dalian He⁴  Yiwen Zhang⁴  Weiwei Liu⁴  Shuliang Jing⁴  Wanying Zhang⁴  Liyang Wu⁴  Xu Zhang⁵  Tao Peng⁵ 

[1] Department of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China;Department of Molecular Therapy, Qianyang Biomedical Research Institute, Guangzhou, China;Guangzhou Women and Children Hospital, Institute of Pediatrics, Guangzhou Medical University, Guangzhou, China;Key Laboratory of Tropical Disease Control of Ministry of Education, Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Institute of Human Virology, Sun Yat-sen University, Guangzhou, China;Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China;

关键词: HIV-1;    Nef;    lovastatin;    MHC-I;    CD4;    SERINC5;   

DOI  :  10.3389/fimmu.2019.02151

来源: DOAJ

【 摘 要 】

Current combined antiretroviral therapy (cART) mainly targets 3 of the 15 HIV proteins leaving many potential viral vulnerabilities unexploited. To purge the HIV-1 latent reservoir, various strategies including “shock and kill” have been developed. A key question is how to restore impaired immune surveillance. HIV-1 protein Nef has long been known to mediate the downregulation of cell-surface MHC-I and assist HIV-1 to evade the immune system. Through high throughput screening of Food and Drug Administration (FDA) approved drugs, we identified lovastatin, a statin drug, to significantly antagonize Nef to downregulate MHC-I, CD4, and SERINC5, and inhibit the intrinsic infectivity of virions. In addition, lovastatin boosted autologous CTLs to eradicate the infected cells and effectively inhibit the subsequent viral rebound in CD4+ T-lymphocytes isolated from HIV-1-infected individuals receiving suppressive cART. Furthermore, we found that lovastatin inhibits Nef-induced MHC-I downregulation by directly binding with Nef and disrupting the Nef–AP-1 complex. These results demonstrate that lovastatin is a promising agent for counteracting Nef-mediated downregulation of MHC-I, CD4, and SERINC5. Lovastatin could potentially be used in the clinic to enhance anti-HIV-1 immune surveillance.

【 授权许可】

Unknown