Research ArticleVACCINES

Dendritic cell–targeted lentiviral vector immunization uses pseudotransduction and DNA-mediated STING and cGAS activation

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Science Immunology  21 Jul 2017:
Vol. 2, Issue 13, eaal1329
DOI: 10.1126/sciimmunol.aal1329

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Successful vaccination through “pseudo” science

Successful vaccines need to deliver antigen as well as stimulate the immune response. Kim et al. examine the mechanisms by which dendritic cell (DC)–targeting lentiviral vectors (LVs) accomplish both of these goals. They found that transduction was not required and that pseudotransduction was sufficient for antigen delivery and immune stimulation. The authors identified two mechanisms behind this effect: Viral fusion induced a PI3K-dependent immune stimulation pathway, and human genomic DNA within the virion preparations activated the STING/cGAS pathway. These data suggest that STING and cGAS agonists could serve as potential vaccine adjuvants.

Abstract

Dendritic cell (DC) activation and antigen presentation are critical for efficient priming of T cell responses. Here, we study how lentiviral vectors (LVs) deliver antigen and activate DCs to generate T cell immunization in vivo. We report that antigenic proteins delivered in vector particles via pseudotransduction were sufficient to stimulate an antigen-specific immune response. The delivery of the viral genome encoding the antigen increased the magnitude of this response in vivo but was irrelevant in vitro. Activation of DCs by LVs was independent of MyD88, TRIF, and MAVS, ruling out an involvement of Toll-like receptor or RIG-I–like receptor signaling. Cellular DNA packaged in LV preparations induced DC activation by the host STING (stimulator of interferon genes) and cGAS (cyclic guanosine monophosphate–adenosine monophosphate synthase) pathway. Envelope-mediated viral fusion also activated DCs in a phosphoinositide 3-kinase–dependent but STING-independent process. Pseudotransduction, transduction, viral fusion, and delivery of cellular DNA collaborate to make the DC-targeted LV preparation an effective immunogen.

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