Table_1_Synthetic Abortive HIV-1 RNAs Induce Potent Antiviral Immunity.docx

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-RNA₅₈) that mimics abortive HIV-1 RNA transcripts. HIV-1 Cap-RNA₅₈ induced potent type I IFN responses in monocyte-derived DCs, monocytes, macrophages and primary CD1c⁺ DCs. Compared with RLR agonist poly-I:C, HIV-1 Cap-RNA₅₈ induced comparable levels of type I IFN responses, identifying HIV-1 Cap-RNA₅₈ as a potent trigger of antiviral immunity. In monocyte-derived DCs, HIV-1 Cap-RNA₅₈ activated the transcription factors IRF3 and NF-κB. Moreover, HIV-1 Cap-RNA₅₈ induced DC maturation and the expression of pro-inflammatory cytokines. HIV-1 Cap-RNA₅₈-stimulated DCs induced proliferation of CD4⁺ and CD8⁺ T cells and differentiated naïve T helper (T_H) cells toward a T_H2 phenotype. Importantly, treatment of DCs with HIV-1 Cap-RNA₅₈ resulted in an efficient antiviral innate immune response that reduced ongoing HIV-1 replication in DCs. Our data strongly suggest that HIV-1 Cap-RNA₅₈ induces potent innate and adaptive immune responses, making it an interesting addition in vaccine design strategies.