Abstract
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-γ-producing cellular responses, but selectively suppressed proinflammatory CD4+ T lymphocytes secreting IL-2 and TNF-α 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 human immunodeficiency virus-1 (HIV-1) pandemic continues to be a serious challenge for global health
Immune correlates for protection are still under investigation, vaccine candidates that are capable of inducing production of broadly neutralizing antibodies and/or broad-spectrum cytotoxic T lymphocyte (CTL) responses are desirable for a successful HIV-1 vaccine [1, 2]
We confirmed that CH25H was up-regulated dramatically in response to stimulation by multiple kinds of TLR agonists in wild-type mice bone marrow-derived macrophages (J2-BMMs), and this up-regulation was abrogated in the Ifnar1−/− BMMs (Figure 1A)
Summary
The human immunodeficiency virus-1 (HIV-1) pandemic continues to be a serious challenge for global health. Immune correlates for protection are still under investigation, vaccine candidates that are capable of inducing production of broadly neutralizing antibodies (bnAbs) and/or broad-spectrum cytotoxic T lymphocyte (CTL) responses are desirable for a successful HIV-1 vaccine [1, 2]. 25-HC plays roles in recruiting monocytes/ macrophages [24], trafficking proinflammatory Th1 lymphocytes [25], and mediating neuroinflammation via activation of NLRP3 inflammasome [26, 27] It is not clear how 25-HC affects HIV/SIV-related innate immunity and adaptive T cell functions. This work is helpful for understanding the immunological mechanism by which CH25H inhibits HIV1/SIV infection, and provides insights into improvements of immunotherapy against HIV-1 infection
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