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

ABSTRACT: Plasmacytoid DCs (pDCs) are innate immune cells that are specialized to produce IFN-? and to activate adaptive immune responses. Although IFN-? inhibits HIV-1 replication in vitro, the production of IFN-? 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-? production upon repeated stimulation, express low levels of maturation molecules, and stimulate weak T cell responses. Persistent IFN-? production by HIV-stimulated pDCs correlated with increased levels of IRF7 and was dependent upon the autocrine IFN-?/? receptor feedback loop. Because it has been shown that early endosomal trafficking of TLR9 agonists causes strong activation of the IFN-? pathway but weak activation of the NF-?B pathway, we sought to investigate whether early endosomal trafficking of HIV, a TLR7 agonist, leads to the IFN-?-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-?-secreting phenotype.

SUBMITTER: O'Brien M 

PROVIDER: S-EPMC3049388 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature