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Spatiotemporal trafficking of HIV in human plasmacytoid dendritic cells defines a persistently IFN-α–producing and partially matured phenotype
Meagan O’Brien, … , David Levy, Nina Bhardwaj
Meagan O’Brien, … , David Levy, Nina Bhardwaj
Published February 21, 2011
Citation Information: J Clin Invest. 2011;121(3):1088-1101. https://doi.org/10.1172/JCI44960.
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Research Article Virology

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

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Abstract

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

Authors

Meagan O’Brien, Olivier Manches, Rachel Lubong Sabado, Sonia Jimenez Baranda, Yaming Wang, Isabelle Marie, Linda Rolnitzky, Martin Markowitz, David M. Margolis, David Levy, Nina Bhardwaj

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