AUTHOR=Stunnenberg Melissa , Sprokholt Joris K. , van Hamme John L. , Kaptein Tanja M. , Zijlstra-Willems Esther M. , Gringhuis Sonja I. , Geijtenbeek Teunis B. H. 

TITLE=Synthetic Abortive HIV-1 RNAs Induce Potent Antiviral Immunity

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.00008

DOI=10.3389/fimmu.2020.00008

ISSN=1664-3224

ABSTRACT=<p>Strong innate and adaptive immune responses are paramount in combating viral infections. Dendritic cells (DCs) detect viral infections via cytosolic RIG-I like receptors (RLRs) RIG-I and MDA5 leading to MAVS-induced immunity. The DEAD-box RNA helicase DDX3 senses abortive human immunodeficiency virus 1 (HIV-1) transcripts and induces MAVS-dependent type I interferon (IFN) responses, suggesting that abortive HIV-1 RNA transcripts induce antiviral immunity. Little is known about the induction of antiviral immunity by DDX3-ligand abortive HIV-1 RNA. Here we synthesized a 58 nucleotide-long capped RNA (HIV-1 Cap-RNA<sub>58</sub>) that mimics abortive HIV-1 RNA transcripts. HIV-1 Cap-RNA<sub>58</sub> induced potent type I IFN responses in monocyte-derived DCs, monocytes, macrophages and primary CD1c<sup>+</sup> DCs. Compared with RLR agonist poly-I:C, HIV-1 Cap-RNA<sub>58</sub> induced comparable levels of type I IFN responses, identifying HIV-1 Cap-RNA<sub>58</sub> as a potent trigger of antiviral immunity. In monocyte-derived DCs, HIV-1 Cap-RNA<sub>58</sub> activated the transcription factors IRF3 and NF-κB. Moreover, HIV-1 Cap-RNA<sub>58</sub> induced DC maturation and the expression of pro-inflammatory cytokines. HIV-1 Cap-RNA<sub>58</sub>-stimulated DCs induced proliferation of CD4<sup>+</sup> and CD8<sup>+</sup> T cells and differentiated naïve T helper (T<sub>H</sub>) cells toward a T<sub>H</sub>2 phenotype. Importantly, treatment of DCs with HIV-1 Cap-RNA<sub>58</sub> resulted in an efficient antiviral innate immune response that reduced ongoing HIV-1 replication in DCs. Our data strongly suggest that HIV-1 Cap-RNA<sub>58</sub> induces potent innate and adaptive immune responses, making it an interesting addition in vaccine design strategies.</p>