Synthetic Abortive HIV-1 RNAs Induce Potent Antiviral Immunity

Abstract

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 58) that mimics abortive HIV-1 RNA transcripts. HIV-1 Cap-RNA 58 induced potent type I IFN responses in monocytederived DCs, monocytes, macrophages and primary CD1c + DCs. Compared with RLR agonist poly-I:C, HIV-1 Cap-RNA 58 induced comparable levels of type I IFN responses, identifying HIV-1 Cap-RNA 58 as a potent trigger of antiviral immunity. In monocyte-derived DCs, HIV-1 Cap-RNA 58 activated the transcription factors IRF3 and NF-κB. Moreover, HIV-1 Cap-RNA 58 induced DC maturation and the expression of proinflammatory cytokines. HIV-1 Cap-RNA 58-stimulated DCs induced proliferation of CD4 + and CD8 + T cells and differentiated naïve T helper (T H) cells toward a T H 2 phenotype. Importantly, treatment of DCs with HIV-1 Cap-RNA 58 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 58 induces potent innate and adaptive immune responses, making it an interesting addition in vaccine design strategies.

The multifaceted nature of HIV latency

“…The transition from an activated state to quiescence may offer a narrow window of opportunity that per-Although the HIV reservoir is usually defined as a pool of cells harboring replication-competent (and therefore intact) genomes, several lines of evidence indicate that defective proviruses, even if not capable of replication, have the ability to produce viral transcripts and viral proteins (45,46). Albeit indirectly, these defective genomes likely contribute to sustained inflammation and T cell activation even after prolonged ART (47,48), which may in turn contribute to HIV persistence by promoting the proliferation of infected T cells (49,50).…”

RNA Helicase DDX3: A Double-Edged Sword for Viral Replication and Immune Signaling

“…Consistently with a critical role of DDX3 during the HIV-1 life cycle, knockdown or inhibition of DDX3 has been described to restrict HIV-1 replication without producing cellular death [103,106,107]. Together with its roles as a proviral factor, DDX3 has also been shown to sense abortive HIV-1 RNA transcripts and trigger a MAVS-dependent type-I interferon signaling in dendritic cells (DCs) [59,108,109]. Consistent with its ability to recognize the 5 end of the HIV-1 full-length RNA [32], DDX3 has been shown to sense a synthetic RNA carrying a m 7 GTP cap structure followed by the first 58 nucleotides of the HIV-1 full-length RNA (the TAR RNA structure) and activate IRF3 and NF-κB, leading to DCs maturation and the expression of pro-inflammatory cytokines (Figure 5b) [109].…”

“…Together with its roles as a proviral factor, DDX3 has also been shown to sense abortive HIV-1 RNA transcripts and trigger a MAVS-dependent type-I interferon signaling in dendritic cells (DCs) [59,108,109]. Consistent with its ability to recognize the 5 end of the HIV-1 full-length RNA [32], DDX3 has been shown to sense a synthetic RNA carrying a m 7 GTP cap structure followed by the first 58 nucleotides of the HIV-1 full-length RNA (the TAR RNA structure) and activate IRF3 and NF-κB, leading to DCs maturation and the expression of pro-inflammatory cytokines (Figure 5b) [109]. However, during viral replication, this DDX3/MAVS-driven immune signaling was blocked through the DC-SIGN/PLK1 pathway, which resulted in an accelerated viral replication [59].…”

Reovirus sensitizes microsatellite stable colorectal cancer to anti-PD-1 treatment via cross-talk in innate and adaptive immune systems

“…36 Engagement of PRRs on DCs induces NF-κB activation, up-regulation of co-stimulatory molecules, and production of cytokines and promotion of cross-priming. 61 PAMPs and DAMPs can also be produced by immunogenic cell death (ICD) of tumor cells induced by reovirus. We are thus confident that reovirus and anti-PD-1 antibody combination is a promising therapeutic approach to convert cold MSS tumors to inflamed immune therapy sensitive tumors.…”