HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells
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
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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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 7

IgG isolated from HIV-infected subjects enhanced IFN production by pDCs.

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IgG isolated from HIV-infected subjects enhanced IFN production by pDCs....
HIV culture strains (A–C) HIVBaL or (D–F) HIVIIIB was incubated with polyclonal IgG isolated from 13 HIV-infected subjects at either 1 or 2 years after seroconversion for 1 to 2 hours and then added to pDCs from at least 5 distinct donors. Supernatants were harvested after 15 hours and assessed for IFN-α. (A and D) IgG isolated from 2 years after infection for 13 subjects ordered from left to right by increasing IFN-α enhancement compared with (A) HIVBaL alone or (D) HIVIIIB alone. The 2 boxes furthest to left of each plot show results with polyclonal IgG isolated from HIV-uninfected subjects and 4E10, as negative and positive controls, respectively. Box plots indicate the median, the 75% and 25% quartiles, and the 95% and 5% outliers (n = 5). All samples were normalized to the HIV-alone conditions indicated by the dashed lines. Conditions were compared using 1-way ANOVA with Dunnett’s multiple comparisons test. *P < 0.05. (B and E) Comparison of IFN-α enhancement by IgG isolated from 1 and 2 years after infection relative to (B) HIVBaL alone or (E) HIVIIIB alone. (C and F) Correlation of gp120 binding versus enhancement of IFN-α by polyclonal IgG from all subjects relative to (C) HIVBaL alone or (F) HIVIIIB alone.