Hiv-1 gp120 activates the stat3/interleukin-6 axis in primary human monocyte-derived dendritic cells

Dendritic cells (DCs) are fundamental for the initiation of immune responses and are important players in AIDS immunopathogenesis. The modulation of DC functional activities represents a strategic mechanism for HIV-1 to evade immune surveillance. Impairment of DC function may result from bystander effects of HIV-1 envelope proteins independently of direct HIV-1 infection. In this study, we report that exposure of immature monocyte-derived DCs (MDDCs) to HIV-1 R5 gp120 resulted in the CCR5-dependent production of IL-6 via MAPK/NF-kB pathways. IL-6 in turn activated STAT3 by an autocrine loop. Concomitantly, gp120 promoted an early activation of STAT3 that further contributed to IL-6 induction. This activation paralleled a concomitant up-regulation of the STAT3 inhibitor PIAS3. Furthermore, the STAT3-regulated microRNAs (miRs) miR-21, miR-155 and miR-181b, were found to be modulated upon gp120 exposure of MDDCs. Notably, neither STAT3/IL-6 pathway activation nor miRs modulation were affected by the CCR5 specific ligand CCL4. Gene ontology and pathway enrichment analysis of functionally relevant targets outlined that these miRs shared common target genes. Furthermore, many of these genes had a fundamental role in the regulation of transcription, and were potentially relevant for the interaction between HIV and DCs. These results identify STAT3 as a key signaling intermediate activated by gp120 in MDDCs and highlight the existence of a novel regulatory network involving STAT3, IL-6 and miRs. HIV-1 gp120 signaling through STAT3 may provide an explanation for the impairment of DC function observed upon HIV exposure.