Journal of Virology最新文献

Globally, the measles virus is making a comeback. Measles still claims the lives of over 100,000 children annually and remains a leading cause of preventable child mortality. Despite the availability of a highly effective and safe measles vaccine since the late 1960s, challenges in vaccine uptake persist. In 2019, Cambodia experienced a resurgence of measles cases, leading to the loss of its elimination status. Many of these cases were reported in geographically isolated and highly mobile communities, such as the floating villages along the Mekong Delta, including Prek Toal. Due to their mobility and geographical isolation, these villages face unique barriers to routine healthcare access and were directly impacted by the 2019 outbreak. To assess vaccination attitudes in this unique population, the Vaccine Attitudes Examination (VAX) scale was adapted to include specific questions about self-vaccination for measles. The modified survey was translated into Khmer and administered to families or caretakers with children living in the floating villages of Prek Toal. The survey results demonstrated broad support for vaccinations among the Prek Toal community, with most respondents expressing confidence in the safety and effectiveness of vaccines. Additionally, while families showed openness to the concept of self-vaccination, there was a strong preference for vaccines to be administered by healthcare professionals. These findings highlight the positive attitudes toward vaccination within this mobile and geographically isolated population, as well as their willingness to consider novel approaches like self-vaccination. Addressing logistical challenges and preferences for healthcare-administered vaccines will be critical in enhancing vaccination strategies in such hard-to-reach communities, ultimately aiding in the fight against measles resurgence.IMPORTANCEMeasles is one of the most transmissible human viruses, and sustaining high vaccination coverage is essential for preventing its resurgence. Remote and mobile communities often have limited, intermittent access to routine health services, yet little is known about their perspectives on vaccination or their openness to new delivery approaches. Cambodia's floating villages represent one such setting, where seasonal changes, mobility, and geographical distance can make routine vaccination more difficult to access. In this study, we examined parental attitudes toward measles vaccination in a floating village and assessed interest in simplified, needle-free vaccination methods. We found high confidence in vaccines and healthcare providers, along with a willingness to consider alternative delivery formats if they are safe and easy to use. These results suggest that logistical challenges rather than hesitancy are key contributors to immunity gaps.

Synaptic pruning is an essential neurodevelopmental process that refines neural circuits by eliminating superfluous or weak synapses, thereby enhancing cognitive functions, including learning and memory. Emerging evidence indicates that viral infections can profoundly influence synaptic processes throughout the nervous system. Viral pathogens have been shown to disrupt synaptic plasticity, alter synaptic protein expression, and dysregulate mechanisms responsible for synaptic elimination. These disruptions are often mediated through the activation of the complement system, inflammatory cytokines, and aberrant expression of postsynaptic density proteins. Depending on the nature and extent of infection, viral interference with synaptic pruning may result in either excessive synapse loss or synaptic retention, both of which are implicated in neuropathological outcomes, such as cognitive decline and neurodevelopmental disorders. This review examines the molecular and cellular mechanisms of synaptic pruning and highlights the impact of various neurotropic viruses on these processes. By elucidating the interplay between viral infections and synaptic pruning, we aim to provide insights into virus-associated neuropathology and inform future research directions and therapeutic strategies in the context of virology and neuroimmunology.

Monoclonal antibodies represent potent biological countermeasures against a wide range of human diseases; however, their clinical application and widespread use are limited by the high cost and complexity of antibody production and manufacturing. The mRNA-lipid nanoparticle (mRNA-LNP) platform offers a versatile strategy for vaccine development and protein-replacement therapies. Since the COVID-19 pandemic, a number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies have been identified, with several granted emergency use authorization for patients. Here, we report the design and generation of mRNA-LNPs encoding two SARS-CoV-2-neutralizing antibodies, 76E1 and LY1404, which, respectively, target the spike protein's fusion peptide (FP) and receptor-binding domain (RBD). We demonstrated that a single intramuscular administration of these mRNA-LNPs in mice resulted in robust antibody production that sustained in circulation for 7-14 days. Furthermore, we evaluated protective effects of these mRNA-delivered antibodies in animal models and showed that a single IM dose of mRNA-LNPs encoding LY1404 or 76E1 conferred significant protection against multiple SARS-CoV-2 variants, including Omicron BQ.1 and Delta, in mice and hamsters. Collectively, these findings highlight the potential of mRNA-based antibody delivery for rapid prevention or treatment of pathogenic infections.IMPORTANCENeutralizing antibodies represent potent biological countermeasures against viral infections. However, the high cost of antibody production restricts its clinical accessibility and large-scale application. The mRNA-lipid nanoparticle (mRNA-LNP) offers a versatile platform for developing vaccines and protein-replacement therapies. In this study, we designed and generated mRNA-LNPs encoding two SARS-CoV-2-neutralizing antibodies, 76E1 and LY1404, which target the viral spike protein's fusion peptide (FP) and receptor-binding domain (RBD), respectively. A single intramuscular administration of mRNA-LNPs encoding LY1404 or 76E1 resulted in rapid antibody production in circulation and conferred protection against multiple strains of SARS-CoV-2 infection in animal models. Our findings highlight the potential of mRNA-based antibody delivery for rapid prevention or treatment of pathogenic infections.

Human papillomavirus (HPV) and Merkel cell polyomavirus (MCPyV) are DNA tumor viruses that cause human cancer. The mechanisms by which HPV and MCPyV oncoproteins induce genomic instability are not well defined. This minireview discusses the influence of these oncoproteins on the repertoire of proteins at replicating DNA, known as the host replisome, and discusses how new technologies like isolation of proteins on nascent DNA (iPOND) can drive the discovery of viral dysregulation of the host replisome to enhance our understanding of viral oncogenesis.

Autographa californica multiple nucleopolyhedrovirus (AcMNPV) E18 (AC143, ODV-E18) is an envelope protein common to both occlusion-derived virions (ODVs) and budded virions (BVs). The e18 gene has been demonstrated to be essential for generating infectious BVs. However, its functional role in virion morphogenesis remains unclear. In this study, we constructed an e18 knockout virus and an e18 repair virus to investigate the effects of e18 deletion on virion morphogenesis. Our data indicated that e18 is required for normal intranuclear microvesicle (IMV) formation and accumulation, for intranuclear envelopment and nuclear egress of nucleocapsids, as well as for embedding of ODVs into occlusion bodies (OBs) and BV production. Additionally, we created and characterized a series of recombinant viruses with truncated e18 of varying lengths to identify domains involved in nuclear translocation and virion morphogenesis. We identified two low-complexity domains (LCDs) in E18, in addition to a known transmembrane domain (TM). The AA30-34 sequence within the TM was found to be essential, but not sufficient for nuclear translocation. However, an α-helix structure encompassing the TM domain proved adequate to mediate a fusion protein's trafficking into the nucleus in the context of additional viral factors. Furthermore, we discovered that the TM was required for the accumulation of IMVs, while both the TM and LCD 1 were necessary for intranuclear envelopment, nuclear egress of nucleocapsids, and the embedding of ODVs into OBs; LCD 2 influenced the processing of IMVs and ODV formation. Both the TM and the two LCDs were essential for BV production.IMPORTANCEThe envelope protein E18 is a conserved component common to both ODV and BV virion types of baculoviruses, yet its functional role in virion morphogenesis remains unclear. This study investigated the e18 gene of Autographa californica multiple nucleopolyhedrovirus, determining that it is essential for normal IMV formation and accumulation, intranuclear envelopment and nuclear egress of nucleocapsids, as well as for the embedding of ODVs into occlusion bodies and BV production. The functional roles of the single TM domain and two LCD domains within E18 during virion morphogenesis were identified. Furthermore, it was found that an α-helix structure encompassing the TM domain is sufficient to facilitate the trafficking of a fusion protein into the nucleus in the context of other viral factors, with AA30-34 being critical for the nuclear import of E18.

Seneca Valley virus (SVV) infection gives rise to severe vesicular diseases in pigs, presenting a substantial threat to the global swine industry. The redox imbalance resulting from oxidative stress is an essential pathogenic mechanism during viral infections. Nevertheless, the regulatory mechanisms of oxidative stress by viral and host factors during SVV infection remain elusive. In this study, we discovered that SVV elicited cellular oxidative stress through the induction of reactive oxygen species production and the suppression of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Our findings indicated that the overexpression of Nrf2/HO-1 exerted a remarkable anti-SVV effect. Conversely, the inhibition of Nrf2/HO-1 expression facilitated the proliferation of SVV. HO-1 metabolic products carbon monoxide and biliverdin inhibit SVV replication. HO-1 promotes type I interferon response and interferon-stimulated gene expressions, which contribute to its antiviral mechanism. Furthermore, our findings reveal that the SVV 3C proteinase targets the Nrf2/HO-1 axis for degradation via caspase pathway, thereby promoting viral replication. Collectively, these results clarify the convoluted molecular mechanisms by which SVV weakens the host's antioxidant defense system and suggest potential targets for therapeutic interventions regarding SVV infections.

Importance: Nrf2 is a crucial redox regulator responsible for initiating the expression of downstream antioxidant genes, including HO-1 and superoxide dismutase. HO-1, an enzyme induced by stress, performs protective roles through the conversion of heme into carbon monoxide, biliverdin, and iron. Nevertheless, the function of Nrf2/HO-1 during Seneca Valley virus (SVV) infection is yet to be clearly defined. In this study, we showed that SVV infection led to a reduction in the expression of Nrf2/HO-1, and the overexpression of Nrf2/HO-1 induced a potent anti-SVV effect. SVV 3C proteinase promoted the caspase-dependent degradation of Nrf2/HO-1. As a result, it attenuated the cell's ability to resist oxidative stress and counteracted the antiviral function of Nrf2/HO-1. Our research further uncovered a novel mechanism through which SVV eludes the host's antiviral effects by disrupting cellular redox balance, offering important targets for preventing and controlling SVV infection.

Avian influenza virus cross-species infection in humans poses a major threat to global public health. Species-specific differences between avian ANP32A and mammalian ANP32 proteins create a natural barrier against viral cross-species infection by directly impairing the functional interaction between the avian-origin viral RNA polymerase and mammalian ANP32 proteins, thereby restricting viral genome replication. The key to overcoming this barrier lies in the adaptation of viral RNA polymerase to host ANP32 family proteins. This mini-review summarizes the mechanisms and variations in influenza virus adaptation to ANP32 proteins across different species. Influenza viruses adapt to species-specific ANP32 proteins through various mutations and display distinct preferences for specific ANP32 family members within the same host. Additionally, alternative splicing variants of ANP32A within a single species further modulate viral RNA polymerase adaptability. Despite this diversity, the underlying interaction mechanism remains conserved: ANP32-polymerase binding is necessary but not sufficient for optimal polymerase activity. This interaction facilitates the formation of asymmetric polymerase dimers and specifically supports viral genome replication, while the step from cRNA to vRNA remains subject to species-specific restrictions. This explains the classic adaptive mechanism of the PB2 E627K mutation, which restores efficient viral genome replication through acid-base pairing with ANP32A. Furthermore, adaptive mutations in emerging strains such as H3N2 canine influenza virus and recent cases of H5N1 in dairy cows underscore the need for continuous viral surveillance and deeper mechanistic studies on virus-ANP32 interactions. Such research is strategically critical for advancing the One Health approach and mitigating future influenza pandemics.

Unlike most enveloped viruses, Herpesviridae distribute cell entry functions across several viral envelope proteins. The prevailing model posits that, upon interaction with the target cell, the activating signal is transmitted from the receptor-binding to the fusion-mediating component in a signaling cascade that involves sequential interactions. However, herpesvirus entry proteins may form complexes throughout fusion. Here, we propose that-by analogy with certain eukaryotic signaling cascades-transmission of the activating signal involves pre-assembled complexes and allosteric effects.

As the most abundant biological entities in the ocean, viruses of microbes play important roles in regulating host population dynamics and influencing biogeochemical cycles. Metagenomic surveys have revealed an astounding reservoir of viral genetic diversity in single-celled marine eukaryotes known as protists, but the vast majority of these viruses have not been directly observed, and information about their protist hosts remains fragmentary. The 2023 discovery of mirusviruses provides a striking example, whereby metagenomic surveys of samples collected by the Tara Oceans expedition led to the discovery of a new phylum of viruses, the Mirusviricota, with remarkable chimeric genomes encoding structural proteins from herpesviruses and enzymes from giant eukaryotic viruses. However, because mirusviruses were detected indirectly by metagenomics, their host range remained unclear, and their biological properties unexplored. Here, we provide new insights into research approaches to identify bona fide protist hosts for marine viruses and characterize virus-host interactions. A greater understanding of these viruses and their natural hosts will unlock opportunities to understand the roles that they play in regulating biogeochemical processes in marine habitats.