Activation of Toll-like receptor 3 inhibits HIV infection of human iPSC-derived microglia.
Peng WangJin-Biao LiuXu WangFeng-Zheng MengQian-Hao XiaoLu LiuJian ZhuWen-Hui HuWen-Zhe HoPublished in: Journal of medical virology (2023)
As a key immune cell in the brain, microglia are essential for protecting the central nervous system (CNS) from viral infections, including HIV. Microglia possess functional Toll-like receptor 3 (TLR3), a key viral sensor for activating interferon (IFN) signaling pathway-mediated antiviral immunity. We, therefore, studied the effect of poly (I:C), a synthetic ligand of TLR3, on the activation of the intracellular innate immunity against HIV in human iPSC-derived microglia (iMg). We found that poly (I:C) treatment of iMg effectively inhibits HIV infection/replication at both mRNA and protein levels. Investigations of the mechanisms revealed that TLR3 activation of iMg by poly (I:C) induced the expression of both type I and type III IFNs. Compared with untreated cells, the poly (I:C)-treated iMg expressed significantly higher levels of IFN-stimulated genes (ISGs) with known anti-HIV activities (ISG15, MxB, Viperin, MxA, and OAS-1). In addition, TLR3 activation elicited the expression of the HIV entry coreceptor CCR5 ligands (CC chemokines) in iMg. Furthermore, the transcriptional profile analysis showed that poly (I:C)-treated cells had the upregulated IFN signaling genes (ISG15, ISG20, IFITM1, IFITM2, IFITM3, IFITM10, APOBEC3A, OAS-2, MxA, and MxB) and the increased CC chemokine signaling genes (CCL1, CCL2, CCL3, CCL4, and CCL15). These observations indicate that TLR3 is a potential therapy target for activating the intracellular innate immunity against HIV infection/replication in human microglial cells. Therefore, further studies with animal models and clinical specimens are necessary to determine the role of TLR3 activation-driven antiviral response in the control and elimination of HIV in infected host cells.
Keyphrases
- toll like receptor
- inflammatory response
- antiretroviral therapy
- immune response
- induced apoptosis
- nuclear factor
- hiv infected
- hiv positive
- signaling pathway
- human immunodeficiency virus
- hiv testing
- lipopolysaccharide induced
- cell cycle arrest
- hiv aids
- hepatitis c virus
- dendritic cells
- endothelial cells
- lps induced
- induced pluripotent stem cells
- sars cov
- men who have sex with men
- liver injury
- pi k akt
- liver fibrosis
- neuropathic pain
- endoplasmic reticulum stress
- genome wide
- brain injury
- gene expression
- drug induced
- white matter
- multiple sclerosis
- dna methylation
- high glucose
- mesenchymal stem cells
- newly diagnosed
- long non coding rna
- spinal cord injury
- heat shock protein
- pluripotent stem cells