Journal
FRONTIERS IN IMMUNOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2018.02686
Keywords
HIV/SIV; inflammation; CTL; immunotherapy; 25-HC
Categories
Funding
- Municipal Health and Medical cooperation innovation Major Project of Guangzhou City [201704020219, 201803040002]
- Science and Technology Planning Project of Guangdong Province [2017A020212005]
- National Science and Technology Major Project of China [2018ZX10731101-002]
- National Natural Science Foundation of China [31370923, 81471606, 31670883, 31870912]
- CAMS Initiative for Innovative Medicine [2016-I2M-1-005]
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Persistent inflammation and extensive immune activation have been associated with HIV-1/SIV pathogenesis. Previously, we reported that cholesterol-25-hydroxylase (CH25H) and its metabolite 25-hydroxycholesterol (25-HC) had a broad antiviral activity in inhibiting Zika, Ebola, and HIV-1 infection. However, the underlying immunological mechanism of CH25H and 25-HC in inhibiting viral infection remains poorly understood. We report here that 25-HC effectively regulates immune responses for controlling viral infection. CH25H expression was interferon-dependent and induced by SIV infection in monkey-derived macrophages and PBMC cells, and 25-HC inhibited SIV infection both in permissive cell lines and primary monkey lymphocytes. 25-HC also strongly inhibited bacterial lipopolysaccharide (LPS)-stimulated inflammation and restricted mitogen-stimulated proliferation in primary monkey lymphocytes. Strikingly, 25-HC promoted SIV-specific IFN-y-producing cellular responses, but selectively suppressed proinflammatory CD4+ T lymphocytes secreting IL-2 and INF-a cytokines in vaccinated mice. In addition, 25-HC had no significant immunosuppressive effects on cytotoxic CD8+ T lymphocytes or antibody-producing B lymphocytes. Collectively, 25-HC modulated both innate and adaptive immune responses toward inhibiting HIV/SIV infection. This study provides insights into improving vaccination and immunotherapy regimes against HIV-1 infection. HIGHLIGHTS - The expression of CH25H was induced by interferon stimulation and SIV infection. - 25-HC strongly inhibited inflammation and restricted mitogen-stimulated proliferation in primary monkey lymphocytes. -25-HC promoted the SIV vaccine-elicited antigen-specific IFN-y-producing cellular responses, but selectively suppressed proinflammatory CD4+ T lymphocytes secreting IL-2 and TNF-alpha cytokines in vaccinated mice. - 25-HC had no significant immunosuppressive effects on cytotoxic CD8+ T lymphocytes or antibody-producing B lymphocytes. - These results demonstrate that 25-HC is beneficial for regulating the inflammation, innate immunity and adaptive immune responses toward inhibiting HIV-1/SIV virus infection.
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