Abstract
Plasmacytoid dendritic cells (pDC) are the major producers of type I interferons (IFNs) in humans and rapidly produce IFN-α in response to virus exposure. Although HIV infection is associated with pDC activation, it is unclear why the innate immune response is unable to effectively control viral replication. We systematically compared the effect of HIV, Influenza, Sendai, and HSV-2 at similar target cell multiplicity of infection (M.O.I.) on human pDC function. We found that Influenza, Sendai, HSV-2 and imiquimod are able to rapidly induce IFN-α production within 4 hours to maximal levels, whereas HIV had a delayed induction that was maximal only after 24 hours. In addition, maximal IFN-α induction by HIV was at least 10 fold less than that of the other viruses in the panel. HIV also induced less TNF-α and MIP-1β but similar levels of IP-10 compared to other viruses, which was also mirrored by delayed upregulation of pDC activation markers CD83 and CD86. BDCA-2 has been identified as an inhibitory receptor on pDC, signaling through a pathway that involves SYK phosphorylation. We find that compared to Influenza, HIV induces the activation of the SYK pathway. Thus, HIV delays pDC IFN-α production and pDC activation via SYK phosphorylation, allowing establishment of viral populations.
Highlights
The innate immune system is essential for the initial detection of invading viruses and subsequent activation of adaptive immunity
In order to standardize for the effects of different viruses on human Plasmacytoid dendritic cells (pDC), we used similar multiplicities of infection (M.O.I.s) of viruses, where the M.O.I. is calculated from the virus infections of their main target cell
PDCs were selected by positive staining for BDCA-2 and CD123, and negative staining for CD14 (Fig. 1A)
Summary
The innate immune system is essential for the initial detection of invading viruses and subsequent activation of adaptive immunity. Plasmacytoid dendritic cells (pDC) are the major producers of type I IFNs in mice and humans. PDCs predominantly utilize TLRs for virus detection and IFN-a production [4], activation occurring through TLRs 7 and 9. Both of these receptors are endosomal and are triggered by ssRNA or double stranded CpG-DNA, respectively [5]. With over 50% of the induced RNA transcripts following TLR7 and TLR9 triggering encoding for type I IFN, the result is production of 3–10 pg/cell of IFNa protein at 24 h, 100-1000X more than any other cell type in the blood [6]. The enhanced capacity for pDCs to produce IFN is related to the high constitutive expression of IRF7 in pDCs, which allows for these cells to bypass the classic autocrine feedback involving IFN-beta (IFN-b) [7,8]
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