Inactivation of Type I IFN Jak-STAT Pathway in EBV Latency

This study investigates the modulation of Type I IFN induction of an antiviral state by HIV. IFNs, including IFN-α, are key innate immune cytokines that activate the JAK/STAT pathway leading to the expression of IFN-stimulated genes. IFN-stimulated gene expression establishes the antiviral state, limiting viral infection in IFN-α-stimulated microenvironments. Our previous studies have shown that HIV proteins disrupt the induction of IFN-α by degradation of IFN-β promoter stimulator-1, an adaptor protein for the up-regulation and release of IFN-α into the local microenvironment via the retinoic acid-inducible gene 1-like receptor signaling pathway. However, IFN-α is still released from other sources such as plasmacytoid dendritic cells via TLR-dependent recognition of HIV. Here we report that the activation of the JAK/STAT pathway by IFN-α stimulation is disrupted by HIV proteins Vpu and Nef, which both reduce IFN-α induction of STAT1 phosphorylation. Thus, HIV would still be able to avoid antiviral protection induced by IFN-α in the local microenvironment. These findings show that HIV blocks multiple signaling points that would lead to the up-regulation of IFN-stimulated genes, allowing more effective replication in IFN-α-rich environments.

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Decision letter for "NCoR1 fine‐tunes type‐I IFN response in cDC1 dendritic cells by directly regulating Myd88‐IRF7 axis under TLR9"

10.1002/eji.202048566/v2/decision1 ◽

2020 ◽

Keyword(s):

Dendritic Cells ◽

Type I ◽

Type I Ifn

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Review for "NCoR1 fine‐tunes type‐I IFN response in cDC1 dendritic cells by directly regulating Myd88‐IRF7 axis under TLR9"

10.1002/eji.202048566/v1/review2 ◽

2020 ◽

Keyword(s):

Dendritic Cells ◽

Type I ◽

Type I Ifn

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PLASMACYTOID DENDRITIC CELLS FUNCTION IN HIV INFECTION

Clinical & Investigative Medicine ◽

10.25011/cim.v31i4.4808 ◽

2008 ◽

Vol 31 (4) ◽

pp. 13

Author(s):

Martin Hyrcza ◽

Mario Ostrowski ◽

Sandy Der

Keyword(s):

Dendritic Cells ◽

Influenza Virus ◽

Hiv Infection ◽

Gene Transcription ◽

Sendai Virus ◽

Plasmacytoid Dendritic Cells ◽

Type I Interferons ◽

Interferon Response ◽

Type I ◽

Type I Ifn

Plasmacytoid dendritic cells (pDCs) are innate immune cells able to produce large quantities of type I interferons (IFN) when activated. Human immunodeficiency virus (HIV)-infected patients show generalized immune dysfunction characterized in part by chronic interferon response. In this study we investigated the role of dendritic cells inactivating and maintaining this response. Specifically we compared the IFN geneactivity in pDCs in response to several viruses and TLR agonists. We hypothesized that 1) the pattern of IFN gene transcription would differ in pDCs treated with HIV than with other agents, and 2) that pDCs from patients from different stages of disease would respond differently to the stimulations. To test these hypotheses, we obtained pDCs from 15 HIV-infected and uninfected individuals and treated freshly isolated pDCs with either HIV (BAL strain), influenza virus (A/PR/8/34), Sendai virus (Cantell strain), TLR7 agonist(imiquimod), or TLR9 agonist (CpG-ODN) for 6h. Type I IFN gene transcription was monitored by real time qPCRfor IFNA1, A2, A5, A6, A8,A17, B1, and E1, and cytokine levels were assayed by Cytometric Bead Arrays forTNF?, IL6, IL8, IL10, IL1?, and IL12p70. pDC function as determined by these two assays showed no difference between HIV-infected and uninfected patients or between patients with early or chronic infection. Specifically, HIV did notinduce type I IFN gene expression, whereas influenza virus, Sendai virus and imiquimod did. Similarly, HIV failed to induce any cytokine release from pDCs in contrast to influenza virus, Sendai virus and imiquimod, which stimulatedrelease of TNF?, IL6, or IL8. Together these results suggest that the reaction of pDCs to HIV virus is quantitatively different from the response to agents such as virus, Sendai virus, and imiquimod. In addition, pDCs from HIV-infected persons have responses similar to pDCs from uninfected donors, suggesting, that the DC function may not be affected by HIV infection.

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