Phosphorylation of STAT1 and NF-κB by human plasmacytoid dendritic cells during HIV-infection (VIR9P.1154)

Abstract

Abstract Plasmacytoid dendritic cells (pDC) are critical for anti-viral immunity. TLR7 and TLR9 allow pDC to recognize viruses and initiate signals leading to IRF7 phosphorylation, which is responsible for IFN-α production, as well as NF-κB phosphorylation, which is responsible for TNF-α and IL-6 induction. During HIV-infection, lower pDC numbers are found, along with impaired IFN-α production. Chronic immune activation is also found, with patients paradoxically displaying an IFN-signature, indicating the presence of IFN-α, and higher serum TNF-α and IL-6. To see if pDC are affected in vivo by IFN-α or TNF-α, we compared baseline p-STAT1 and p-NF-κB in pDC in HIV-patients vs healthy controls. At baseline, HIV-patient vs. healthy pDC showed a trend towards elevated p-STAT1, while p-NF-κB levels were similar. HIV-patient pDC phosphorylated STAT1 and NF-κB less than healthy controls in response to IFN-α and TNF-α, respectively. In response to viruses, HIV-patient pDC phosphorylated STAT1 more than healthy controls. Despite normal production of TNF-α and IL-6, HIV-patient pDC were unable to phosphorylate NF-κB in response to viruses, suggesting that other mechanisms exist for TNF-α and IL-6 induction. In conclusion, impaired NF-κB phosphorylation by HIV-patient pDC suggest that they are immunologically exhausted and this can lead to a number of downstream effects on protein expression. In contrast, enhanced p-STAT1 in response to viruses can drive the IFN-signature seen in HIV-patients.