TY - JOUR
T1 - HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells
AU - Veenhuis, Rebecca T.
AU - Freeman, Zachary T.
AU - Korleski, Jack
AU - Cohen, Laura K.
AU - Massaccesi, Guido
AU - Tomasi, Alessandra
AU - Boesch, Austin W.
AU - Ackerman, Margaret E.
AU - Margolick, Joseph B.
AU - Blankson, Joel N.
AU - Chattergoon, Michael A.
AU - Cox, Andrea L.
N1 - Funding Information:
This work was supported by the National Institute of Allergy and Infectious Diseases (R01 AI108403, R01 AI102691, U01 AI35042, and K08 AI10269). Flow cytometry experiments were performed in the Becton Dickinson Immune Function Laboratory at the Johns Hopkins Bloomberg School of Public Health. The facility is supported in part by the Johns Hopkins University Center for AIDS Research (CFAR): 5P30AI094189-04 (Chaisson). LKC was supported by T32 GM007309 (NIH).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI95375
DO - 10.1172/JCI95375
M3 - Article
C2 - 29083319
AN - SCOPUS:85037107592
SN - 0021-9738
VL - 127
SP - 4352
EP - 4364
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -