HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells
Rebecca T. Veenhuis, … , Michael A. Chattergoon, Andrea L. Cox
Rebecca T. Veenhuis, … , Michael A. Chattergoon, Andrea L. Cox
Published October 30, 2017
Citation Information: J Clin Invest. 2017;127(12):4352-4364. https://doi.org/10.1172/JCI95375.
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Research Article AIDS/HIV Inflammation

HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells

Abstract

Type I IFN production is essential for innate control of acute viral infection; however, prolonged high-level IFN production is associated with chronic immune activation in HIV-infected individuals. Although plasmacytoid DCs (pDCs) are a primary source of IFN, the mechanisms that regulate IFN levels following the acute phase are unknown. We hypothesized that HIV-specific Ab responses regulate late IFN production. We evaluated the mechanism through which HIV-activated pDCs produce IFN as well as how both monoclonal HIV-specific Abs and Abs produced in natural HIV infection modulated normal pDC sensing of HIV. We found that HIV-induced IFN production required TLR7 signaling, receptor-mediated entry, fusion, and viral uncoating, but not endocytosis or HIV life cycle stages after uncoating. Abs directed against the HIV envelope that do not interfere with CD4 binding markedly enhanced the IFN response, irrespective of their ability to neutralize CD4+ T cell infection. Ab-mediated enhancement of IFN production required Fc γ receptor engagement, bypassed fusion, and initiated signaling through both TLR7 and TLR9, which was not utilized in the absence of Ab. Polyclonal Abs isolated from HIV-infected subjects also enhanced pDC production of IFN in response to HIV. Our data provide an explanation for high levels of IFN production and immune activation in chronic HIV infection.

Authors

Rebecca T. Veenhuis, Zachary T. Freeman, Jack Korleski, Laura K. Cohen, Guido Massaccesi, Alessandra Tomasi, Austin W. Boesch, Margaret E. Ackerman, Joseph B. Margolick, Joel N. Blankson, Michael A. Chattergoon, Andrea L. Cox

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Figure 1

Type I IFN induction by HIV requires receptor-mediated entry, not endocytosis or productive infection.

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Type I IFN induction by HIV requires receptor-mediated entry, not endocy...
After culture with HIVBaL, (A) human pDCs were harvested and assessed for type I IFN and TNF-α mRNA expression and (B) IFN-α protein production was measured at multiple time points. UNT, untreated with HIV. (A and B) One representative experiment, completed in triplicate, is shown. (C) Human pDCs were cultured with either HIVBaL culture supernatant or with purified HIVBaL for 15 hours,then assessed for IFN-α protein production (n = 3). (D) Human pDCs were cultured with endocytosis (n = 4) or (E) HIV life cycle inhibitors for 1 hour, followed by the addition of HIVBaL for 15 hours (n = 4). Supernatants were harvested and assessed for IFN-α protein production. Each data point indicates the average IFN-α production from 1 donor’s pDCs tested in at least duplicate and normalized to the media-alone condition. Error bars and gray boxes represent the SEM and the mean, respectively. Conditions were compared using 1-way ANOVA with Dunnett’s multiple comparisons test. *P < 0.01.