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 8

Suggested mechanism by which HIV-specific Abs that don’t block CD4 binding enhance type I IFN-s.

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Suggested mechanism by which HIV-specific Abs that don’t block CD4 bindi...
Representative diagrams of (A) IFN production by pDCs exposed to HIV and (B) enhanced IFN production by pDCs exposed to HIV preincubated with envelope-specific Abs that do not block CD4 binding. The 2 conditions diverge at 2 steps. First, the addition of Abs allows sensing of HIV without membrane fusion and through engagement of the FcγR2A; however, the engagement of both CD4 and CCR5 is still required. Secondly, in the presence of Ab, both endosomal TLRs, 7 and 9, sense the virus, while TLR9 plays no role in the absence of Ab. Inhibitors, Abs, and/or methods used to elucidate each step of the mechanism are listed here and numbered in the diagrams (A and B). Only steps of HIV sensing that differ when Ab is present are numbered in B. 1. anti-human CD4 Ab; 2. Maraviroc; 3. Enfuvirtide (T20); 4. CypA; 5. TLR 7 and TLR9 oligo inhibitors; 6. MAPK p38 inhibitor and Phosflow detection of phosphorylated p38; 7. IKKβ inhibitor and Phosflow detection of phosphorylated NF-kB p65; 8. Phosflow detection of p-IRF7; 9. Quantitative reverse-transcriptase PCR (RTqPCR) detection of type I IFN mRNA; 10. ELISA detection of type I IFN protein. The following are shown in B only: 11. gp120 and gp41 mAbs and polyclonal IgG; 12. VRC01 variants, deglycosylated Abs, and FcR2-blocking Abs.