Dufrasne, F. E. | bioRxiv Science

bioRxiv2025

The cellular Activating Protein 1 cFos regulates Influenza A virus replication

Previous research has demonstrated that Influenza A virus (IAV) infection activates AP-1 transcription factors as part of the antiviral response. In this study, we identified cFos as the most upregulated AP-1 transcription factor during IAV infection in A549 human lung cells. Surprisingly, the knockdown of cFos resulted in impaired IAV replication. Fluorescence microscopy and functional analyses indicated that cFos is implicated in IAV infection through its nuclear function, rather than its cytoplasmic role as an activator of lipid synthesis. The investigation into the role of cFos in IAV infection revealed increased apoptosis and elevated interferon-{beta} mRNA levels in cFos-knockdown A549 cells during IAV infection. This suggests that cFos may enhance cell survival and reduce interferon-{beta} expression during infection, thereby facilitating IAV proliferation. Furthermore, the levels of viral NA mRNA and the expression of late viral proteins NA and M2 decreased upon cFos knockdown. Overall, this study identifies cFos as a proviral factor for IAV, through the modulation of innate immunity and apoptosis during infection, and potentially by supporting the viral transcription. Author SummaryInfluenza A viruses pose a significant threat to global public health. Understanding the interaction between the virus and host is essential for the development of antiviral therapies. We identified cFos, a cellular Activating Protein-1, as a pro-viral factor for influenza A viruses. cFos was found to enhance cell survival and regulate the expression of certain cytokines during viral infection. Our findings also suggested a potential role for cFos in the viral transcription, especially of the viral proteins expressed late in the viral cycle.

microbiology↗

bioRxiv2020

HIV-1 and HIV-2 differentially regulate NF-κB activity during the late stages of the replication cycle through BST-2/tetherin antagonism

HIV-2 is the second causative agent of AIDS and is commonly considered as an attenuated form of retroviral infection. Most of HIV-2-infected individuals display a slow-progressing disease, lower viral loads and a stronger immunological control of viral infection as compared with HIV-1-infected patients. The main hypothesis that could explain the difference of disease progression between HIV-1 and HIV-2 implies a more efficient T cell-mediated immunity in the control of HIV-2 infection. Herein, we investigate the effects of the HIV-2 envelope glycoprotein (Env) and its antitetherin function in the NF-{kappa}B signaling pathway during single-round infection of CD4+ T cells. First, we report an essential role of the Env cytoplasmic tail (CT) in the activation of this signaling pathway and we also demonstrate that the HIV-2 Env CT activates NF-{kappa}B in a TRAF6-dependent but TAK1-independent manner. Further, we show that HIV-2 reference strains and clinical isolates are unable to completely inhibit NF-{kappa}B mainly via the Env-mediated BST-2/tetherin antagonism in the late stages of the viral replication cycle in CD4+ T cells, in striking contrast to the HIV-1 Vpu-mediated counteraction of tetherin. We observe that this inability of HIV-2 to suppress NF-{kappa}B signaling pathway promotes stimulation of numerous genes involved in the antiviral immune response, such as il-6, il-21 and ifn-{beta} genes. Therefore, HIV-1 and HIV-2 differentially regulate the NF-{kappa}B-induced antiviral immune response mainly through the BST-2/tetherin antagonism. These new insights highlight molecular mechanisms determining, at least partly, the distinct immune control and disease outcomes of HIV-1 and HIV-2 infections. IMPORTANCEThis study explores how HIV-1 and HIV-2 diverge in their regulation of the NF-{kappa}B signaling pathway. We revealed that HIV-2 fails to completely inhibit NF-{kappa}B activity, thereby inducing a stronger antiviral response than HIV-1. We demonstrated that the ability to antagonize the cellular restriction factor BST-2/tetherin largely governs the regulation of the NF-{kappa}B pathway: at the late stages of the viral replication cycle, HIV-1 Vpu blocks this pathway whereas HIV-2 Env does not. We also demonstrated that several NF-{kappa}B-targeted genes are upregulated in CD4+ T cells infected with HIV-2, but not with HIV-1. This stronger NF-{kappa}B-induced antiviral response may explain the better immune control of HIV-2 infection and the differences between HIV-1 and HIV-2 pathogenesis. Moreover, we observed in this study that non-pathogenic isolates of HIV-2 have an impaired NF-{kappa}B inhibitory capacity compared to pathogenic ones.

microbiology↗