LPS and HIV-1 induce a mature phenotype in human plasmacytoid dendritic cells and enhance their programmed death ligand-1 expression (VIR1P.970)

Abstract

Abstract Aberrant immune activation and immune exhaustion are features characteristic of chronic HIV infection. Elevated plasma LPS levels resulting from disruption of gut mucosal integrity during HIV infection have been implicated as a major factor contributing to immune activation. In chronic HIV-1 infection immune exhaustion molecules PD-1 and its ligand PD-L1 negatively regulate the function of exhausted CD8 T cells. The pDC constitute only a minor portion of the PBMC population, but are crucial contributors to the innate as well as adaptive immune response. We have confirmed our previous results that pDC express low levels of TLR4 and respond to LPS. We undertook this study to examine the influence of LPS on virally stimulated pDC maturation and PD-L1 expression and mechanisms thereof. In order to do so we primed pDC with LPS prior to stimulation with HIV. We observed that LPS enhanced HIV-1-induced pDC maturation (CD83 and CD40 expression) and PD-L1 expression. PD-L1 was up-regulated on mature pDC specifically by LPS and HIV combination treatment versus individual treatment with LPS or HIV. The combination treatment specifically induced co-expression of PD-L1 with positive co-stimulatory molecule CD86 but not CD80. Additionally, LPS enhanced CD4 expression on pDC but depressed HIV-1 induced CXCR4 and CCR5 expression. Together, these results indicate that in response to HIV stimulation, pDC adopt a tolerogenic phenotype (i.e. PD-L1-positive) and LPS helps drive this.