Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-α-producing and partially matured phenotype

Plasmacytoid DCs (pDCs) are innate immune cells that are specialized to produce IFN-alpha and to activate adaptive immune responses. Although IFN-alpha inhibits HIV-1 replication in vitro, the production of IFN-alpha by HIV-activated pDCs in vivo may contribute more to HIV pathogenesis than to protection. We have now shown that HIV-stimulated human pDCs allow for persistent IFN-alpha production upon repeated stimulation, express low levels of maturation molecules, and stimulate weak T cell responses. Persistent IFN-alpha production by HIV-stimulated pDCs correlated with increased levels of IRF7 and was dependent upon the autocrine IFN-alpha/beta receptor feedback loop. Because it has been shown that early endosomal trafficking of TLR9 agonists causes strong activation of the IFN-alpha pathway but weak activation of the NF-kappa B pathway, we sought to investigate whether early endosomal trafficking of HIV, a TLR7 agonist, leads to the IFN-alpha-producing phenotype we observed. We demonstrated that HIV preferentially traffics to the early endosome in human pDCs and therefore skews pDCs toward a partially matured, persistently IFN-alpha-secreting phenotype.