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

• Published in: The Journal of clinical investigation Vol. 121; no. 3; pp. 1088 - 1101
• Main Authors: O'Brien, Meagan, Manches, Olivier, Sabado, Rachel Lubong, Baranda, Sonia Jimenez, Wang, Yaming, Marie, Isabelle, Rolnitzky, Linda, Markowitz, Martin, Margolis, David M, Levy, David, Bhardwaj, Nina
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2011
• Subjects: Cytokines - metabolism; Dendritic cells; Dendritic Cells - virology; Genetic aspects; Health aspects; HIV (Viruses); HIV - metabolism; HIV Infections - metabolism; Humans; Immune System; Interferon alpha; Interferon-alpha - metabolism; NF-kappa B - metabolism; Phenotype; Physiological aspects; RNA, Messenger - metabolism; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins - metabolism; Time Factors; Toll-Like Receptor 9 - agonists; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI44960

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.