|Title||HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Authors||Veenhuis RT, Freeman ZT, Korleski J, Cohen LK, Massaccesi G, Tomasi A, Boesch AW, Ackerman ME, Margolick JB, Blankson JN, Chattergoon MA, Cox AL|
|Journal||J Clin Invest|
|Date Published||2017 Dec 01|
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.
|Alternate Journal||J. Clin. Invest.|
|PubMed Central ID||PMC5707144|
|Grant List||U01 AI035042 / AI / NIAID NIH HHS / United States |
T32 GM007309 / GM / NIGMS NIH HHS / United States
R01 AI102691 / AI / NIAID NIH HHS / United States
P30 AI094189 / AI / NIAID NIH HHS / United States
R01 AI108403 / AI / NIAID NIH HHS / United States
HIV-antibody complexes enhance production of type I interferon by plasmacytoid dendritic cells.