Mechanisms of enhanced TRAIL, CD86, and CD40 expression by plasmacytoid dendritic cells from HIV-infected subjects (VIR5P.1027)

Abstract

Abstract Plasmacytoid dendritic cells (pDC) are critical in viral immunity via their production of IFN-α and presentation of antigen. In HIV+ subjects, pDC decline impairs immune defense, while chronic in vivo stimulation of pDC contributes to immune activation. Here, we aimed to further explore pDC dysfunction in HIV+ subjects. We confirmed that pDC from HIV+ subjects have increased TRAIL, CD86, and CD40 expression compared to healthy donors. pDC from both HIV+ and healthy subjects upregulated TRAIL, CD86, and CD40 in response to overnight HIV- and HSV-stimulation. However, pDC from HIV+ subjects with CD4 >200 showed increased TRAIL, CD86, and CD40 upregulation compared to healthy donors and HIV+ subjects with CD4 <200. pDC from healthy donors were then used to explore how expression of these molecules occurs. Inhibition of endosomal acidification blocked TRAIL, CD86, and CD40 in virus-stimulated pDC. TLR7 inhibition in HIV-stimulated pDC partially inhibited this expression. While TLR9 blockage also inhibited CD40 expression by HSV-stimulated pDC, there was no effect on CD86 and TRAIL. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-α were able to enhance TRAIL expression by HIV-stimulated pDC. Despite upregulation of CD86, HIV- stimulated pDC from healthy donors were poor inducers of allogeneic CD4 T cell expansion. We conclude that pro-inflammatory cytokines, along with TLR signaling, “prime” pDC in HIV-infected individuals to express TRAIL, CD86, and CD40.