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Assessing the Innate Sensing of HIV-1 Infected CD4+ T Cells by Plasmacytoid Dendritic Cells Using an Ex vivo Co-culture System.
Published on: September 1, 2015
HIV and HIV-Tat inhibit LPS-induced IL-27 production in human macrophages by distinct intracellular signaling
Niranjala Gajanayaka1,2, Shifawn O'Hara1,2, Yulia Konarski1,2
1Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
Abstract:
Monocyte-derived Mϕs (MDMs) from HIV-infected patients and MDM infected in vitro with HIV exhibit a reduced ability to secrete various cytokines, including IL-12. Recently, IL-27, an IL-12 family cytokine, was shown to inhibit HIV replication in Mϕ. Whether HIV infection or HIV accessory protein(s) impact IL-27 production in Mϕs remains unknown. Herein, we show that in vitro HIV infection, as well as intracellular HIV-Tat (Tat) and Tat peptides, inhibit LPS-induced IL-27 production in human MDMs, suggesting impairment of the TLR4 signaling pathway. To understand the signaling pathways governing HIV or Tat-mediated inhibition of LPS-induced IL-27 production, we first demonstrated that p38 MAPK, PI3K, Src-homology region 2 domain-containing tyrosine phosphatase 1 (SHP-1), and Src kinases regulate LPS-induced IL-27 production in MDMs. Tat caused down-regulation of TNFR-associated factor (TRAF)-6 and inhibitor of apoptosis 1 (cIAP-1) and subsequently decreased phosphorylation of downstream PI3K and p38 MAPKs, which were implicated in LPS-induced IL-27 production. Whereas SHP-1 and Src kinases regulated LPS-induced IL-27 production, Tat did not inhibit these kinases, suggesting that they were not involved in Tat-mediated inhibition of LPS-induced IL-27 production. In contrast to Tat, in vitro HIV infection of MDM inhibited LPS-induced IL-27 production via inhibition of p38 MAPK activation. Overall, HIV and Tat inhibit LPS-induced IL-27 production in human macrophages via distinct mechanisms: Tat through the inhibition of cIAP-1-TRAF-6 and subsequent inhibition of PI3K and p38 MAPKs, whereas HIV through the inhibition of p38 MAPK activation.
Insights
Human immunodeficiency virus (HIV) and its Tat protein impair interleukin-27 (IL-27) production in macrophages. This impacts immune responses by distinct pathways, affecting HIV replication and treatment strategies.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Monocyte-derived macrophages (MDMs) from HIV-infected individuals show reduced cytokine secretion, including IL-12.
- Interleukin-27 (IL-27), an IL-12 family cytokine, inhibits HIV replication in macrophages.
- The effect of HIV infection or its proteins on IL-27 production in macrophages is unknown.
Purpose of the Study:
- To investigate whether HIV infection or HIV accessory proteins impact IL-27 production in human MDMs.
- To elucidate the signaling pathways involved in HIV or Tat-mediated inhibition of IL-27 production.
Main Methods:
- In vitro infection of human MDMs with HIV.
- Treatment of MDMs with HIV-Tat and Tat peptides.
- Analysis of Toll-like receptor 4 (TLR4) signaling pathway components.
- Assessment of p38 MAPK, PI3K, SHP-1, and Src kinase activity.
- Evaluation of TNFR-associated factor (TRAF)-6 and inhibitor of apoptosis 1 (cIAP-1) expression.
Main Results:
- In vitro HIV infection and HIV-Tat inhibit lipopolysaccharide (LPS)-induced IL-27 production in human MDMs.
- HIV-Tat down-regulates cIAP-1 and TRAF-6, decreasing PI3K and p38 MAPK phosphorylation.
- HIV infection inhibits LPS-induced IL-27 production by suppressing p38 MAPK activation.
- SHP-1 and Src kinases regulate IL-27 production but are not involved in Tat-mediated inhibition.
Conclusions:
- HIV and its Tat protein inhibit LPS-induced IL-27 production in human macrophages through distinct mechanisms.
- Tat inhibits IL-27 production via cIAP-1-TRAF-6 and downstream PI3K/p38 MAPK pathways.
- HIV inhibits IL-27 production by directly suppressing p38 MAPK activation.
