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

PLoS One. 2015 Jun 19;10(6):e0129425. doi: 10.1371/journal.pone.0129425. eCollection 2015.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cytokines / metabolism*
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Dynamins / metabolism
  • Endocytosis
  • HIV Infections / immunology
  • HIV Infections / metabolism
  • HIV Infections / virology
  • Humans
  • Inflammation Mediators / metabolism*
  • Lipopolysaccharide Receptors / metabolism
  • Lymphocyte Antigen 96 / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Multiprotein Complexes
  • NF-kappa B / metabolism*
  • Protein Binding
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Toll-Like Receptor 4 / metabolism
  • tat Gene Products, Human Immunodeficiency Virus / metabolism*


  • Cytokines
  • Inflammation Mediators
  • Lipopolysaccharide Receptors
  • Lymphocyte Antigen 96
  • Multiprotein Complexes
  • NF-kappa B
  • SOCS1 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Toll-Like Receptor 4
  • tat Gene Products, Human Immunodeficiency Virus
  • Dynamins