HIV delays IFN-α production from human plasmacytoid dendritic cells and is associated with SYK phosphorylation.
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.
Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
Calvin C
CC
Lo
Jordan A
JA
Schwartz
Dylan J
DJ
Johnson
Monica
M
Yu
Nasra
N
Aidarus
Shariq
S
Mujib
Erika
E
Benko
Martin
M
Hyrcza
Colin
C
Kovacs
Mario A
MA
Ostrowski
D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D006678:HIV / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009975:Orthomyxoviridae / Q000276:immunology / Q000502:physiology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D013045:Species Specificity; D000072377:Syk Kinase; D013997:Time Factors; D014779:Virus Replication
D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase