The productive infection of influenza A virus (IAV) depends on host factors. However, the involvement of long non-coding RNAs (lncRNAs) in IAV infection remains largely uninvestigated. In this work, we have discovered a human lncRNA, named lncRNA-PAAN (PA-associated noncoding RNA) that enhances IAV replication. The level of lncRNA-PAAN increases upon infection of IAV, but not other viruses, nor interferon treatment, suggesting specific up-regulation of lncRNA-PAAN expression by IAV. Silencing lncRNA-PAAN significantly decreases IAV replication through impairing the activity of viral RNA-dependent RNA polymerase (RdRp). This function of lncRNA-PAAN is a result of its association with viral PA protein, a key component of IAV RNA polymerase complex. Consequently, depletion of lncRNA-PAAN prevents the formation of functional RdRp. Together, these results suggest that lncRNA-PAAN promotes the assembly of viral RNA polymerase, thus warranting efficient viral RNA synthesis. Elucidating the functions of lncRNAs in IAV infection is expected to advance our understanding of IAV pathogenesis and open new avenues to the development of novel anti-IAV therapeutics.

Recent studies have identified host long noncoding RNAs (lncRNAs) as key regulators of host-virus interactions during viral infection. The influenza A virus (IAV) remains a serious threat to public health and economic stability. It is well known that thousands of lncRNAs are differentially expressed upon IAV infection, some of which regulate IAV infection by modulating the host innate immune response, affecting cellular metabolism, or directly interacting with viral proteins. Some of these lncRNAs appear to be required for IAV infection, but the molecular mechanisms are not completely elucidated. In this review, we summarize the roles of host lncRNAs in regulating IAV infection, and provide an overview of the lncRNA-mediated regulatory network. The goal of this review is to stimulate further research on the function of both well-established and newly discovered lncRNAs in IAV infection.

Long noncoding RNAs (lncRNAs) have been reported to modulate immune responses to viral infections. However, it remains largely unexplored how viruses exploit host lncRNAs to promote viral replication. Here, we found that an lncRNA, called lnc-ALOX12, is upregulated specifically in cells infected by influenza A virus (IAV). Lnc-ALOX12 promotes IAV infection through associating with IAV RNA polymerase subunit PB2, sustaining the interaction between PB2 and importin-α/β, thus warranting PB2 nuclear import and efficient viral RNA synthesis. Importantly, avian influenza A virus needs to mutate its PB2 protein in order to hijack human lnc-ALOX12 for efficient viral RNA synthesis in mammal cells. Therefore, our data support the dependence of IAV replication on host lncRNAs. This dependence is species-specific and acts as a barrier to cross-species transmission of avian influenza viruses.

The effective antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently needed around the world. The 3C-like protease (3CL^pro) of SARS-CoV-2 plays a pivotal role in virus replication; it also has become an important therapeutic target for the infection of SARS-CoV-2. In this work, we have identified Darunavir derivatives that inhibit the 3CL^pro through a high-throughput screening method based on a fluorescence resonance energy transfer (FRET) assay in vitro. We found that the compounds 29# and 50# containing polyphenol and caffeine derivatives as the P2 ligand, respectively, exhibited favorable anti-3CL^pro potency with EC50 values of 6.3 μM and 3.5 μM and were shown to bind to SARS-CoV-2 3CL^pro in vitro. Moreover, we analyzed the binding mode of the DRV in the 3CL^pro through molecular docking. Importantly, 29# and 50# exhibited a similar activity against the protease in Omicron variants. The inhibitory effect of compounds 29# and 50# on the SARS-CoV-2 3CL^pro warrants that they are worth being the template to design functionally improved inhibitors for the treatment of COVID-19.