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Isolation, Transfection, and Culture of Primary Human Monocytes
Published on: December 16, 2019
HIV infection suppresses TLR3 activation-mediated antiviral immunity in microglia and macrophages
Hang Liu1,2, Run-Hong Zhou2, Yu Liu2
1School of Basic Medical Sciences, Wuhan University, Wuhan, China.
Abstract:
Monocytic-lineage cells in the central nervous system (CNS), including microglia and brain resident macrophages, are the key players in the CNS innate immunity against viral infections, including human immunodeficiency virus (HIV). However, these cells also serve as the major targets and reservoirs for HIV in the CNS. To address the question of how HIV can establish persistent infection in the target cells in the CNS, we examined whether HIV has the ability to counteract Toll-like receptor 3 (TLR3) activation-mediated antiviral immunity in microglia and macrophages. We observed that HIV latently infected microglial cells (HC69·5) expressed reduced levels of TLR3 and TLR3 activation-mediated interferons (IFN-α/β and IFN-λ) as compared with the uninfected control cells (C20). In addition, HIV infection of primary human macrophages suppressed the expression of TLR3 and the IFNs. HIV infection also inhibited the expression of the antiviral IFN-stimulated genes (ISGs) and the HIV-restriction miRNAs. Mechanistically, HIV infection inhibited the phosphorylation of IFN regulatory factors (IRF3 and IRF7) and signal transducer and activator of transcription proteins (STAT1 and STAT3) in both HIV latently infected microglia and acutely infected macrophages. These findings provide previously unrecognized and sound mechanisms for HIV infection and persistence in the primary target and reservoir cells in the brain.
Insights
Human immunodeficiency virus (HIV) evades the brain's immune defenses by suppressing Toll-like receptor 3 (TLR3) signaling in microglia and macrophages. This allows for persistent HIV infection in the central nervous system (CNS).
Area of Science:
- Neuroimmunology
- Virology
- Infectious Diseases
Background:
- Monocytic lineage cells, including microglia and macrophages, are crucial for central nervous system (CNS) innate immunity against viral infections like human immunodeficiency virus (HIV).
- These cells are also primary targets and reservoirs for HIV within the CNS.
- Understanding how HIV establishes persistent CNS infections is critical for developing effective treatments.
Purpose of the Study:
- To investigate whether HIV can counteract Toll-like receptor 3 (TLR3) activation-mediated antiviral immunity in microglia and macrophages.
- To elucidate the mechanisms by which HIV establishes persistent infection in these key CNS cells.
Main Methods:
- Comparison of TLR3 expression and TLR3-induced interferon production in latently HIV-infected microglial cells versus uninfected controls.
- Assessment of TLR3 and interferon expression in primary human macrophages following HIV infection.
- Analysis of antiviral interferon-stimulated genes (ISGs) and HIV-restriction microRNAs (miRNAs) expression.
- Investigation of the phosphorylation status of key signaling proteins (IRF3, IRF7, STAT1, STAT3) in infected cells.
Main Results:
- Latently HIV-infected microglial cells showed reduced TLR3 and TLR3-mediated interferon (IFN-α/β, IFN-λ) levels compared to controls.
- HIV infection suppressed TLR3 and interferon expression in primary human macrophages.
- HIV infection inhibited the expression of antiviral ISGs and HIV-restriction miRNAs.
- HIV infection impaired the phosphorylation of IRF3, IRF7, STAT1, and STAT3 in both latently infected microglia and acutely infected macrophages.
Conclusions:
- HIV actively counteracts TLR3-mediated antiviral immunity in microglia and macrophages within the CNS.
- Suppression of TLR3 signaling and downstream antiviral pathways contributes to HIV persistence in the brain.
- These findings reveal novel mechanisms underlying HIV's ability to establish and maintain infection in CNS target cells.
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