Modulation of Antiviral Immunity and Therapeutic Efficacy by 25-Hydroxycholesterol in Chronically SIV-Infected, ART-Treated Rhesus Macaques

Chunxiu Wu; Jin Zhao; Ruiting Li; Fengling Feng; Yizi He; Yanjun Li; Runhan Huang; Guangye Li; Heng Yang; Genhong Cheng; Ling Chen; Feng Ma; Pingchao Li; Caijun Sun

doi:10.1007/s12250-021-00407-6

Modulation of Antiviral Immunity and Therapeutic Efficacy by 25-Hydroxycholesterol in Chronically SIV-Infected, ART-Treated Rhesus Macaques

Virol Sin. 2021 Oct;36(5):1197-1209. doi: 10.1007/s12250-021-00407-6. Epub 2021 May 31.

Authors

Chunxiu Wu^{1

2}, Jin Zhao^{3

4}, Ruiting Li^{3

4}, Fengling Feng^{3

4}, Yizi He^{1

2}, Yanjun Li^{3

4}, Runhan Huang³, Guangye Li⁵, Heng Yang^{6

7}, Genhong Cheng^{6

7

8}, Ling Chen^{1

2}, Feng Ma^{9

10}, Pingchao Li¹¹, Caijun Sun^{12

13}

Affiliations

¹ State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, 510530, China.
² University of Chinese Academy of Sciences, Beijing, 100049, China.
³ School of Public Health (Shenzhen), Sun Yat-Sen University, Guangdong, 518107, China.
⁴ Key Laboratory of Tropical Disease Control, Sun Yat-Sen University, Ministry of Education, Guangzhou, 514400, China.
⁵ Guangdong Landau Biotechnology Co. Ltd, Guangzhou, 510700, China.
⁶ Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China.
⁷ Suzhou Institute of Systems Medicine, Suzhou, 215123, China.
⁸ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, 90095, USA.
⁹ Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, China. maf@ism.pumc.edu.cn.
¹⁰ Suzhou Institute of Systems Medicine, Suzhou, 215123, China. maf@ism.pumc.edu.cn.
¹¹ State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health (GIBH), Chinese Academy of Sciences, Guangzhou, 510530, China. li_pingchao@gibh.ac.cn.
¹² School of Public Health (Shenzhen), Sun Yat-Sen University, Guangdong, 518107, China. suncaijun@mail.sysu.edu.cn.
¹³ Key Laboratory of Tropical Disease Control, Sun Yat-Sen University, Ministry of Education, Guangzhou, 514400, China. suncaijun@mail.sysu.edu.cn.

Abstract

Cholesterol-25-hydroxylase (CH25H) and its enzymatic product 25-hydroxycholesterol (25HC) exert broadly antiviral activity including inhibiting HIV-1 infection. However, their antiviral immunity and therapeutic efficacy in a nonhuman primate model are unknown. Here, we report that the regimen of 25HC combined with antiretroviral therapy (ART), provides profound immunological modulation towards inhibiting viral replication in chronically SIV_mac239-infected rhesus macaques (RMs). Compared to the ART alone, this regimen more effectively controlled SIV replication, enhanced SIV-specific cellular immune responses, restored the ratio of CD4/CD8 cells, reversed the hyperactivation state of CD4⁺ T cells, and inhibited the secretion of proinflammatory cytokines by CD4⁺ and CD8⁺ T lymphocytes in chronically SIV-infected RMs. Furthermore, the in vivo safety and the preliminary pharmacokinetics of the 25HC compound were assessed in this RM model. Taken together, these assessments help explain the profound relationship between cholesterol metabolism, immune modulation, and antiviral activities by 25HC. These results provide insight for developing novel therapeutic drug candidates against HIV-1 infection and other related diseases.

Keywords: 25-hydroxycholesterol (25HC); Antiretroviral therapy (ART); HIV; Macaque; SIV.

MeSH terms

Animals
Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
CD4-Positive T-Lymphocytes
HIV Infections* / drug therapy
Hydroxycholesterols
Macaca mulatta
Simian Acquired Immunodeficiency Syndrome* / drug therapy
Simian Immunodeficiency Virus*

Substances

Antiviral Agents
Hydroxycholesterols
25-hydroxycholesterol