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

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

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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12250-021-00407-6.