Virologica Sinica最新文献

Dengue virus (DENV) is a mosquito-borne pathogen responsible for a spectrum of illnesses, including dengue fever, dengue hemorrhagic fever, and dengue shock syndrome. Nearly half of the global population is at risk of DENV infection, making it a pressing public health issue worldwide. The limited cross-protection among the four DENV serotypes (DENV1-4) and the phenomenon of antibody-dependent enhancement (ADE) have posed significant challenges to the development of effective dengue vaccines. Furthermore, there are currently no specific antiviral treatments available. This review provides an overview of DENV's key characteristics, clinical manifestations, and recent advancements in antiviral drug development- including the repurposing of approved drugs, peptide-based antiviral agents, therapeutic antibodies, natural products with antiviral potential, and host factor inhibitors- aiming to offer critical insights to inform strategies for managing and preventing dengue outbreaks.

Incomplete immune reconstitution occurs in 10%-40% of antiretroviral therapy (ART)-treated human immunodeficiency virus (HIV) patients. This subset of immunological non-responders (INRs) has yet to undergo a comprehensive analysis of immunological profiles, and no definitive cytological diagnosis has been established. In this study, we comparatively analyzed the immunological profiles of INRs, immunological responders (IRs), and healthy control individuals (HCs) via single-cell RNA sequencing (scRNA-seq) and single-cell T-cell receptor (TCR) repertoire sequencing of peripheral blood mononuclear cells (PBMCs), and identified a relatively small population of mucosal-associated invariant T (MAIT) cells in INRs. This finding was recapitulated in rhesus macaques infected with simian immunodeficiency virus (SIV). Specifically, the population of the naïve MAIT cell subtype was significantly lower in INRs than in IRs, and the majority of MAIT cells were CD8⁺ cell subsets. Further characteristic analysis of MAIT cells via the transcriptome revealed decreased expression of cytotoxicity-related genes in INRs, while displaying increased expression of genes involved in TGF-β receptor signaling. In summary, by conducting a comparative analysis, this study revealed a correlation between the decreased proportion of naïve MAIT cells and impaired immune reconstitution in INRs. This finding highlights a particular cell subset that may play a pivotal role in the incomplete immune reconstitution, and suggests a plausible cellular target for the modulation of INRs.

Coronaviruses (CoVs) are a large family of human and animal pathogens that cause significant health and economic burdens worldwide. Thapsigargin (Tg) is a plant-derived sesquiterpene lactone with potent antiviral effects; however, the underlying mechanism remains unclear. Here, we show that Tg exhibited strong antiviral activity against the neurotropic swine CoV porcine hemagglutinating encephalomyelitis virus (PHEV) both in vivo and in vitro. Tg also exhibited inhibitory activity against other three swine coronaviruses in cell lines. Specifically, Tg treatment significantly inhibited the replication and transcription of genomic RNA in the viral life cycle but did not directly inactivate PHEV. Transcriptome analysis and glycolysis/mitochondrial stress testing confirmed that Tg alters intracellular metabolic flux, and suppresses glycolysis and oxidative phosphorylation (OXPHOS). Furthermore, metabolic reprogramming is associated with the antiviral effect of Tg and is required for productive PHEV infection. Overall, our findings highlight that Tg plays a crucial role in combating viral infections by targeting host energy metabolism shared by pathogenic microorganisms, suggesting that targeting key nodes of host metabolic processes may be a strategy for designing antiviral drugs against coronaviruses.

Oncolytic virus therapy is a promising strategy for cancer treatment. Herpes simplex virus type 1 (HSV-1) has been successfully used in oncolytic virotherapy. In the present research, we applied an HSV-1 synthetic genomics platform to construct two oncolytic viruses, oHSV-1.1 and oHSV-1.2. oHSV-1.1 had the virulence gene ICP34.5 and ICP47 deleted for attenuation, and oHSV-1.2 was additionally armed with murine granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-12 (IL-12). The oncolytic viruses were evaluated in vitro and in an immunocompetent murine melanoma model. The animal experiments confirmed that both oncolytic viruses displayed antitumor efficacy, including inhibiting tumor growth and prolonging overall survival. Compared with oHSV-1.1, oHSV-1.2 demonstrated superior tumor growth suppression and enhanced antitumor efficacies, as evidenced by increased tumor cell apoptosis, cytotoxic T cells and macrophages infiltration, IFN-γ production, and upregulation of inflammatory-related gene expression. Our research highlights the potential of oncolytic HSV-1 expressing both GM-CSF and IL-12 for melanoma therapy, and provides a promising strategy for further development of oncolytic virotherapy.

Human enterovirus A71 (EV-A71) is a major causative agent of hand, foot and mouth disease (HFMD), which poses a significant public health threat, particularly among young children. Mitochondrial antiviral signaling protein (MAVS) and interferon regulatory factor 3 (IRF3) are vital proteins for the induction of type I interferons (IFN-I) and downstream interferon-stimulated genes (ISGs) during EV-A71 infection. While posttranslational modifications are known to critically influence viral infection processes, the mechanisms by which EV-A71 exploits host deubiquitinases (DUBs) for immune evasion remain poorly understood. In this study, we demonstrated that EV-A71 infection upregulated ubiquitin-specific protease 5 (USP5) expression. Knockdown of USP5 not only inhibited EV-A71 replication but also observably increased the production of IFN-I and ISGs. Furthermore, USP5 also regulated the replication of EV-D68 and CVA16 and the production of IFN-I and ISGs. Mechanistically, USP5 physically interacted with MAVS and IRF3 and reduced the K63-linked polyubiquitination of MAVS and IRF3. Conversely, USP5 knockdown increased the K63-linked polyubiquitination of MAVS and IRF3, thereby accelerating the phosphorylation of IRF3 and increasing IFN-I production during EV-A71 infection. Furthermore, pharmacological inhibition of USP5 with the small-molecule inhibitor PR-619 significantly potentiated the antiviral effects of IFN against EV-A71. Collectively, our findings reveal a previously unrecognized role of USP5 in facilitating EV-A71 immune evasion by dampening MAVS- and IRF3-mediated antiviral signaling. These insights provide a novel therapeutic avenue for combating EV-A71 infection through targeted modulation of the USP5-IRF3 axis.

Crimean-Congo hemorrhagic fever virus (CCHFV) is a highly pathogenic tick-borne virus that causes severe hemorrhagic fever with high mortality rates in humans. No licensed vaccines or efficacious antiviral therapies are currently available. Here, we identified seven heavy chain antibodies targeting CCHFV Gc, which consist of heavy-chain variable domain (VHH) fused to human IgG1 Fc region (VHH-Fc). These VHH-Fc antibodies exhibited neutralizing activity against both recombinant vesicular stomatitis virus (VSV)-vectored CCHFV pseudoviruses and CCHFV transcription- and entry-competent virus-like particles (tecVLPs). Among these, N025 achieved the most potent pseudovirus neutralization, while N013 showed remarkable efficacy in tecVLP systems, with IC₅₀ values of 22.7 ng/mL and 33.0 ng/mL, respectively. AlphaFold3 structural predictions revealed that all characterized VHH-Fc antibodies target epitopes within Domain II of the Gc protein, with partial or complete overlap with the fusion loop region. Alanine scanning mutagenesis confirmed the functional significance of these epitopes, with N013 showing the highest binding energy change (ΔΔG = 25.36 kcal/mol) and moderate competition with a known fusion loop-targeting antibody. Sequence conservation analysis across representative CCHFV strains from different genetic lineages demonstrated complete conservation of the N013 and N025 epitopes, suggesting potential for broad-spectrum neutralizing activity. Together, our findings provide a novel strategy for developing CCHFV therapeutics and identify promising antibody candidates that could inform future broad-spectrum antiviral development efforts.

The transcription factor Sex-determining region Y-box protein 3 (SOX3) is well known for its critical roles in sex determination and cell differentiation; however, its function in antiviral innate immunity remains unexplored. This study uncovered how SOX3, induced by viral infections, modulates type I interferon (IFN-I) responses. RNA sequencing, quantitative PCR, and immunoblot analysis collectively revealed that SOX3 overexpression suppresses virus-induced interferon beta 1(IFN-β) promoter activation and significantly inhibits the expression of key antiviral interferon-stimulated genes (ISGs), including ISG15 and interferon induced protein with tetratricopeptide repeats 1 (IFIT1). Conversely, the knockdown of SOX3 enhanced IFN-β production and ISGs expression, confirming its role as a negative regulator of antiviral immunity. Mechanistically, chromatin immunoprecipitation sequencing (ChIP-seq) identified SOX3 binding specifically at the AKT serine/threonine kinase 1 (AKT1) locus. Further analysis demonstrated that SOX3 directly upregulates AKT1 expression, subsequently increasing phosphorylation and inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN). Inactivation of PTEN inhibited interferon regulatory factor 3 (IRF3) nuclear translocation, leading to reduced IFN-β expression. Thus, our findings uncover a previously uncharacterized SOX3-AKT1-PTEN signaling axis in the regulation of antiviral innate immunity, providing new insights into immune evasion strategies and highlighting potential therapeutic targets to enhance antiviral responses.