ArticlePloS one2015
HIV-1 Tat Protein Induces Production of Proinflammatory Cytokines by Human Dendritic Cells and Monocytes/Macrophages through Engagement of TLR4-MD2-CD14 Complex and Activation of NF-κB Pathway.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it.
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- Molecular, immunological and oncogenic mechanisms of cervical cancer mediated by HPV/HIV co-infection, clinical implication and management.Infectious agents and cancer · 2025Review
- SLC38A9 is directly involved in Tat-induced endolysosome dysfunction and senescence in astrocytes.Life science alliance · 2025Article
- Mouse Models of HIV-Associated Atherosclerosis.International journal of molecular sciences · 2025Review
- Viruses and the Brain-A Relationship Prone to Trouble.Viruses · 2025Review
- Nef is a key player in neuroinflammation and myelin impairment associated with neuroHIV.Frontiers in neurology · 2025Article
- Innate immune memory in chronic HIV and HIV-associated neurocognitive disorders (HAND): potential mechanisms and clinical implications.Journal of neurovirology · 2024Review
- Suppression of HIV-TAT and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.Journal of neurovirology · 2024Article
- The cell biology of HIV-1 latency and rebound.Retrovirology · 2024Review
- Fentanyl dysregulates neuroinflammation and disrupts blood-brain barrier integrity in HIV-1 Tat transgenic mice.Journal of neurovirology · 2024Article
- Examining Chronic Inflammation, Immune Metabolism, and T Cell Dysfunction in HIV Infection.Viruses · 2024Review
- Role of HIV-1 Tat Protein Interactions with Host Receptors in HIV Infection and Pathogenesis.International journal of molecular sciences · 2024Review
- TLR4 signalling: the key to controlling EV71 replication and inflammatory response.Frontiers in cellular and infection microbiology · 2024Article
- Suppression of HIV and cocaine-induced neurotoxicity and inflammation by cell penetrable itaconate esters.bioRxiv : the preprint server for biology · 2023Article
- Toll-like Receptor Response to Human Immunodeficiency Virus Type 1 or Co-Infection with Hepatitis B or C Virus: An Overview.International journal of molecular sciences · 2023Review
- Role of ubiquitin regulatory X domain‑containing protein 3B in the development of hepatocellular carcinoma (Review).Oncology reports · 2023Review
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Authors and funding
8 authors.
Funding
Abstract
We recently reported that the human immunodeficiency virus type-1 (HIV-1) Tat protein induced the expression of programmed death ligand-1 (PD-L1) on dendritic cells (DCs) through a TLR4 pathway. However, the underlying mechanisms by which HIV-1 Tat protein induces the abnormal hyper-activation of the immune system seen in HIV-1 infected patients remain to be fully elucidated. In the present study, we report that HIV-1 Tat protein induced the production of significant amounts of the pro-inflammatory IL-6 and IL-8 cytokines by DCs and monocytes from both healthy and HIV-1 infected patients. Such production was abrogated in the presence of anti-TLR4 blocking antibodies or soluble recombinant TLR4-MD2 as a decoy receptor, suggesting TLR4 was recruited by Tat protein. Tat-induced murine IL-6 and CXCL1/KC a functional homologue of human IL-8 was abolished in peritoneal macrophages derived from TLR4 KO but not from Wt mice, confirming the involvement of the TLR4 pathway. Furthermore, the recruitment of TLR4-MD2-CD14 complex by Tat protein was demonstrated by the activation of TLR4 downstream pathways including NF-κB and SOCS-1 and by down-modulation of cell surface TLR4 by endocytosis in dynamin and lipid-raft-dependent manners. Collectively, these findings demonstrate, for the first time, that HIV-1 Tat interacts with TLR4-MD2-CD14 complex and activates the NF-κB pathway, leading to overproduction of IL-6 and IL-8 pro-inflammatory cytokines by myeloid cells from both healthy and HIV-1 infected patients. This study reveals a novel mechanism by which HIV-1, via its early expressed Tat protein, hijacks the TLR4 pathway, hence establishing abnormal hyper-activation of the immune system.
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