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Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor– viral RNA interactions
Anne-Sophie Beignon, … , Jeffrey D. Lifson, Nina Bhardwaj
Anne-Sophie Beignon, … , Jeffrey D. Lifson, Nina Bhardwaj
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3265-3275. https://doi.org/10.1172/JCI26032.
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Research Article AIDS/HIV

Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor– viral RNA interactions

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Abstract

HIV-1 directly activates human plasmacytoid DCs (pDCs) by upregulating the expression of costimulatory and MHC molecules and maturation markers, increasing T cell stimulatory activity, and inducing the production of type I interferons and TNF-α. A consequence of this activation is the bystander maturation of myeloid DCs and overall enhancement of antigen-presenting function. However, little is known about the mechanism(s) of pDC activation by HIV-1. Here we demonstrate by in vitro studies that IFN-α production by pDC in response to HIV-1 requires at least 2 interactions between the cell and virus. Initially, envelope-CD4 interactions mediate endocytosis of HIV-1, as demonstrated through the use of inhibitors of binding, fusion, endocytosis, and endosomal acidification. Subsequently, endosomally delivered viral nucleic acids, particularly RNA, stimulate pDCs through TLRs, as activation is reproduced with purified genomic RNA but not viral RNA packaging–deficient HIV-1 and blocked with different inhibitory TLR ligands. Finally, by using genetic complementation, we show that TLR7 is the likely primary target. Viral RNA rather than DNA in early retrotranscripts appears to be the active factor in HIV-1 that induces IFN-α secretion by pDCs. Since the decline in pDCs in chronic HIV-1 infection is associated with high viral loads and opportunistic infections, exploiting this natural adjuvant activity of HIV-1 RNA might be useful in the development of vaccines for the prevention of AIDS.

Authors

Anne-Sophie Beignon, Kelli McKenna, Mojca Skoberne, Olivier Manches, Ida DaSilva, Daniel G. Kavanagh, Marie Larsson, Robert J. Gorelick, Jeffrey D. Lifson, Nina Bhardwaj

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Figure 5

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HIV RNA stimulates pDCs but not MDCs. (A) Flow cytometry–sorted pDCs wer...
HIV RNA stimulates pDCs but not MDCs. (A) Flow cytometry–sorted pDCs were exposed overnight to recombinant wild-type or mutant NC SSHS/SSHS HIV-1NL4-3 at the doses of 900 or 300 ng p24CA Eq/ml. As controls, pDCs were cultured with CpGA ODN or HIV-1MN. (B) BDCA-4+ cells were stimulated with 10,000 times more copies of pNL4-3 than the amount present in 900 ng p24CA/ml of HIV-1NL4-3, in the circular (cir) and linearized (lin) forms and after formulation with DOTAP. Low doses of CpGA and CpGB ODNs (1 μg/ml) and R848 (1 μM) were used as controls. Flow cytometry–sorted blood pDCs (C) and MDCs (D) were treated overnight with HIV-1MN RNA, microvesicle-derived RNA (Mv RNA), or with RNA40 and RNA41 mixed with DOTAP as controls. HIV-1MN and Mv RNA were preincubated with RNase prior to formulation with DOTAP. Flow cytometry–sorted pDCs (E) and MDCs (F) were cultured overnight with 900 ng p24CA/ml of wild-type HIV-1NL4-3 or pseudotyped VSV-G HIV-1NL4-3. Concentrations of IFN-α (ng/ml) produced by pDCs and TNF-α (pg/ml) produced by pDCs and MDCs were determined by ELISA. CD83 expression was measured by flow cytometry (the percentage of positive cells is indicated in bold and the mean of fluorescence intensity underlined).
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