Current Opinion in Virology

Leveraging plant virus–vector molecular interactions for innovative vector and disease control

2026-12-31

Bryony C Bonning

Innate immunity-mediated inflammation and immunopathogenesis in HSV-1-infected encephalitis

2026-12-31

Sheng Yang, Yangkun Shen, Chunfu Zheng

HSV-1 encephalitis (HSE) remains a devastating viral infection of the central nervous system despite effective antiviral therapy. Increasing evidence indicates that disease outcome is not determined by viral replication alone but by how innate immunity is calibrated within the brain. Studies of host susceptibility in childhood HSE have identified brain-intrinsic antiviral mechanisms, referring to central nervous system (CNS)-localized innate immune pathways that enable resident brain cells to sense and restrict HSV-1 infection, particularly TLR-dependent interferon responses, neuron-associated restriction factors, and other CNS-resident innate immune mechanisms. Host innate immune responses initially contribute to viral restriction, whereas excessive or unresolved activation can promote inflammatory amplification and long-term neurological injury. In parallel, HSV-1-mediated immune remodeling may weaken antiviral control and alter the subsequent inflammatory trajectory. Here, HSE is discussed as a dynamic immunopathological disorder in which protective innate immunity can transition into pathogenic neuroinflammation. Building upon these observations, we propose that host-directed therapeutic strategies should shift from uniform immune modulation toward stage-specific immune recalibration on the basis of viral control, antiviral competence, inflammatory persistence, and tissue repair.

Molecular dialogues in plant rhabdovirus–host interactions

2026-12-31

Kaili Wu, Wenlin Yang, Zhenghe Li

Rab GTPases in antiviral innate immunity: mechanisms and potential therapeutics

2026-12-31

Ananya Pathak, Preston Nguyen, Athul Mohanram, Junji Xing

Mass mortality events in aquatic mammals caused by avian influenza viruses

2026-12-31

Monica Mirolo, Martin Ludlow, Albert Osterhaus

In recent decades, mass mortality events (MMEs) among aquatic mammals have been caused by morbillivirus or avian influenza virus (AIV) infections. Thus far, AIV infections have been predominantly associated with direct or indirect contact with infected birds, while mammal-to-mammal AIV transmission has not been formally proven in most cases. However, amino acid changes in the HA or PB2 RNA segments previously identified as 'mammalian-adapting mutations' have been documented during AIV epizootics in aquatic mammals. Such mutations are known to increase infectivity and/or virulence of AIV in mammalian species, including humans. Epizootics caused by low-pathogenic AIV (LPAIV) are typically self-limiting respiratory disease outbreaks. In contrast, the ongoing panzootic caused by highly pathogenic AIV (HPAIV) subtype A(H5N1) clade 2.3.4.4b is associated with severe neurological disease and mortality in infected pinniped and cetacean species. The available serological data suggest that enzootic circulation of AIV in aquatic mammals is limited. LPAIV-specific antibodies have been detected in pinniped species only during documented flu outbreaks and have then decreased to undetectable levels, while no AIV-specific antibodies have been detected following recent HPAIV A(H5N1) infections. Since direct interventions in wild pinnipeds are limited, AIV surveillance and investigations into the genetic and phenotypic characteristics of AIVs associated with MMEs in aquatic mammals will be essential to better understand the risk that these viruses pose to often endangered animal populations, as well as to public health.

Molecular grappling: the complex interplay involving human herpesviruses, small ubiquitin-like modifier (SUMO), and the host immune system

2026-12-31

Sairam Dasika, Janna M Bigalke

SUMOylation regulates critical cellular processes, including DNA repair, transcription, and immune responses. Human herpesviruses (HHVs) have evolved mechanisms to hijack the SUMO pathway, promoting viral replication, immune evasion, and establishment of latency. This review explores how HHVs manipulate the host SUMOylation machinery, detailing key viral proteins and their effects, as well as antiviral defense mechanisms.

Non-coding RNAs: cross-kingdom regulators of plant–virus–vector interactions in complex agroecosystems

2026-12-31

Dinesh S Pujara, Clare L Casteel

Challenges in AI-based structural modeling of host–pathogen protein interactions

2026-12-31

Konstantin Gilep, Jan Kosinski

Pathogens depend heavily on their hosts, a relationship driven by molecular interactions. Among the diverse molecular classes involved, proteins and protein-protein interactions (PPIs) serve as the pillars of these infectious processes. Driven by opposing natural selection pressures, with one protein adapting to escape the interaction and the other adapting to maintain it, host and pathogen proteins coevolve in this arms race. With the advent of artificial intelligence-driven structural prediction methods, initiated by AlphaFold, highly accurate structural modeling of PPIs has become feasible. Yet, host-pathogen PPIs remain difficult to model with these approaches. In this review, we describe the current state of host-pathogen structural modeling, describe recent studies, and discuss how pushing current methods to their limits might improve success rates.

Editorial overview: Viral zoonosis

2026-12-31

Christiane Riedel, Solene Denolly, Claudia Schulz

Determinants of orthoflavivirus tropism in humans: from cellular entry to organ-specific pathogenesis

2026-12-31

Jule A Russow, Luca D Bertzbach, Wing Hang Ip, Stephanie Pfaender

Orthoflaviviruses, including dengue virus, tick-borne encephalitis virus, West Nile virus, Zika virus, Japanese encephalitis virus, and yellow fever virus, cause a wide spectrum of diseases in humans despite sharing a similar genomic organization. These viruses pose a growing global threat as they are spreading widely, treatment options remain limited, and both climate change and expanding mosquito populations increase the risk of outbreaks worldwide. This review summarizes the determinants of their human tropism, the capacity to infect specific cell types, tissues, and organs. We synthesized current knowledge on how viral factors, including host factor utilization and immune cell trafficking, shape tropism across multiple layers. Central to this process are sequential host barriers that govern infection, including viral attachment, internalization, and replication. Understanding these determinants is essential for informing strategies to mitigate the global burden of these medically important pathogens.

Mechanistic insights into potyviral and cucumoviral subversion of plant resistance

2026-12-31

John P Carr

Potyviruses and cucumoviruses (exemplified by cucumber mosaic virus (CMV)) are highly divergent taxa of plant-infecting positive-sense RNA viruses. However, they face similar challenges. They must overcome host antiviral resistance mechanisms, for example, RNA silencing or resistance mediated by the phytohormone salicylic acid, and they must do this across a very diverse range of host species. Although in some hosts potyviruses and CMV are seedborne, they are predominantly transmitted by aphid vectors. Both have acquired mechanisms for subverting host defences, particularly those controlled by jasmonic acid, to manipulate vector behaviour and increase transmission. This article compares how CMV and potyviruses took distinct evolutionary paths to overcome these common challenges. Potyviruses diverged into numerous distinct viral species to exploit different hosts and co-opted many gene products, including P1, HC-Pro, NIa, VPg, 6K2 and NIb, to effector roles. In contrast, CMV strains show less divergence but still exploit wide host ranges, and predominantly use the 2b counter-defence protein for subverting and manipulating host responses.

Editorial overview: Novel vaccine adjuvants: advances in mechanism, design, and translation

2026-12-31

Kouji Kobiyama, Ken J Ishii

The discovery and development of small molecule immune potentiators (SMIPs) as next-generation vaccine adjuvants, the creation of AS37

2026-12-31

Elvira Ianni, Daniela Stranges, Derek T O’Hagan

Lessons from mycobacteria: development and design of Mincle-targeting adjuvants

2026-09-30

Shigenari Ishizuka, Sho Yamasaki

Host defense against intracellular pathogens, including viruses and mycobacteria, requires not only antibody production but also T cell-mediated cellular immunity, which is often overlooked in current vaccine strategies. C-type lectin receptors (CLRs) are one of the innate immune receptors that can promote adaptive immunity through the induction of co-stimulatory molecules or soluble factors in antigen-presenting cells. This review focuses on the potential of CLR ligands, specifically those for macrophage-inducible C-type lectin (Mincle), as next-generation vaccine adjuvants. Mincle recognizes glycolipids such as trehalose dimycolate (TDM) from mycobacteria and induces Th1 and Th17 responses, crucial mechanisms for countering intracellular pathogens. We discuss the structural basis of the ligand-recognition modes of Mincle, which involves both sugar-binding pockets and hydrophobic grooves to accommodate acyl chains. Additionally, we discuss efforts to develop synthesizable and highly active ligands such as trehalose dibehenate (TDB) and lipidated brartemicin (C18Brar). We further highlight novel strategies to enhance immunostimulatory efficacy, including the concept of dual-ligand adjuvants (e.g. C18Brar-muramyl dipeptide conjugate) and the use of nanoparticle/liposome delivery systems (e.g. CAF formulations). Collectively, these advancements highlight the potential of Mincle ligands as candidates for effective adjuvants. For clinical application, species-specific differences in adjuvant effectiveness between humans and experimental animals must be addressed, and highly functionalized Mincle ligands must be developed. Future research should establish Mincle-targeting ligands as indispensable tools for the development of next-generation vaccines.

Human genetics of HIV infection

2026-09-30

Abraham Awada, Christian W Thorball, Valeriia Timonina, Mary Carrington, Paul J McLaren, Jacques Fellay

Human Immunodeficiency Virus Type 1 (HIV-1) continues to pose a significant global public health challenge. Marked inter-individual variability in susceptibility to infection, viral load, and disease progression has long highlighted an important role for host genetic factors. To date, only a small number of germline loci show consistent, reproducible effects on HIV-1 control, most notably CCR5 and HLA class I genes. Recent studies have refined the mechanistic basis of these associations, clarifying how CCR5 regulation and specific HLA-B residues shape CD8⁺ T-cell and natural killer cell responses. Beyond these loci, emerging population-specific associations, including variants at the CHD1L/PRKAB2 locus, underscore the importance of studying diverse populations and highlight novel pathways influencing viral replication and evolution. In parallel, attention has shifted toward somatic genetic variation and aging-related processes in people living with HIV-1. HIV-1 infection and chronic immune activation are associated with genomic instability, accelerated accumulation of mitochondrial DNA mutations, telomere shortening, and increased prevalence of clonal hematopoiesis, processes that may contribute to inflammation and non-communicable comorbidities despite effective viral suppression. As well, the growing application of polygenic risk scores to predict cardiometabolic and renal disease in treated populations has implications for precision HIV-1 medicine. As universal antiretroviral therapy reduces opportunities to study natural HIV-1 progression, future genetic research will increasingly focus on how host germline and somatic variation influence therapeutic outcomes and viral reservoir dynamics to shape long-term health outcomes and emerging treatment strategies.

The molecular arms race: mechanisms of fungal antiviral defense and viral counterstrategies

2026-09-30

Gudam Kwon, Jisuk Yu, Kook-Hyung Kim

Programming systemic and mucosal immunity through co-adjuvant-based prime-boost vaccination

2026-09-30

Satoshi Uematsu

STING agonists as next-generation vaccine adjuvants: mechanisms, opportunities, and challenges

2026-09-30

Burcu Temizoz, Ken J Ishii

Vaccine adjuvants shape the magnitude and quality of adaptive immune responses by engaging innate sensing pathways. Among emerging platforms, agonists of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway have gained significant attention due to their capacity to induce type I interferon responses, enhance antigen cross-presentation, and promote robust CD4⁺ and CD8⁺ T cell immunity. This review outlines the major classes of natural and synthetic STING agonists, their mechanisms of action, and their applications as vaccine adjuvants and stand-alone immunoprophylactic agents, with a particular focus on viral infections and virus-associated cancers. We also discuss their roles in cancer immunotherapy and highlight key translational challenges, including species-specific differences, human STING polymorphisms, and safety considerations related to excessive or prolonged pathway activation. Finally, we summarize emerging strategies aimed at optimizing STING agonist design, delivery, and precision targeting to improve safety and efficacy in next-generation vaccine and immunotherapy development.

Targeting innate immune sensors for intranasal vaccine adjuvant design

2026-09-30

Dorian C Dederko, Ed C Lavelle

While injectable vaccines can prevent respiratory pathogens from causing severe disease, their ability to elicit protective local immunity in the respiratory mucosa is more limited. For viral pathogens, infection outcome is often determined at the site of entry, where innate immune sensing within the airway mucosa precedes and conditions adaptive immune responses. At these surfaces, epithelial cells and antigen-presenting cells express a wide repertoire of pattern recognition receptors (PRRs), positioning innate immune activation as a central determinant of vaccine efficacy and durability of mucosal immunity. Recent advances in mucosal immunology facilitate the progression of mucosal vaccine development from empirical formulation toward mechanism-informed targeting of innate immune pathways. This review highlights emerging evidence supporting targeted engagement of cytosolic and endosomal PRRs to enhance intranasal vaccine efficacy. We focus on the cyclic GMP-AMP synthase-stimulator of interferon genes (STING) pathway, highlighting how spatially and temporally constrained STING activation can drive interferon-mediated antiviral immunity, enhance antigen presentation and promote tissue-resident T cells. We also discuss how complementary targeting of endosomal PRRs, including TLR3 and TLR9, further reinforces antiviral programming and adaptive immunity at mucosal sites.

Noncanonical expression mechanisms in orthoflaviviruses

2026-09-30

Samuel Donaire-Carpio, Adam Moundib, Chloë Delon, Nolwenn Jouvenet

Beyond brain fog: viral proteins as convergent drivers of neuroinflammation and proteinopathy

2026-09-30

Christopher Käufer, Rebecca Kotzur, Kristina Lau, Franziska Richter

Post-viral neurological syndromes, such as post-acute sequelae of COVID-19, present a paradox of severe symptoms despite minimal CNS viral replication. The 'protein-as-pathogen' model, where shed viral proteins act as soluble neurotoxins, is now central to understanding this phenomenon. This review presents the opinion that the most critical recent developments are not that these proteins are toxic, but how their mechanisms converge. We synthesize evidence from the last two years showing that proteins from diverse, highly infectious virus families with zoonotic potential (e.g. Coronaviridae, Flaviviridae, Orthomyxoviridae) engage shared host pathways. We focus on two convergent mechanisms: (1) the activation of glial Toll-like receptor (TLR)4/TLR2 signaling, which initiates a chronic neuroinflammatory cascade, and (2) the disruption of host proteostasis, which seeds neurodegenerative proteinopathies like alpha-synuclein and tau aggregation. This framework positions post-viral syndromes as mechanistically related disorders and identifies pan-viral therapeutic targets, such as TLR inhibitors and autophagy activators.

When structural rationales fall short: revisiting the immunogenicity of herpesvirus prefusion and postfusion glycoprotein B

2026-09-30

Julia Nentwig, Kay Grünewald, Benjamin Vollmer

The concept of stabilising viral fusion proteins in their prefusion conformation to focus immunogenicity has driven vaccine research across many viruses. However, for herpesviruses, recent findings suggest that this approach may not yield the hoped-for immunological benefits, underscoring the importance of critically assessing the structure of target proteins. This review examines the structural and functional characteristics of herpesvirus glycoprotein B (gB), a key component in herpesvirus entry and fusion, and evaluates recent immunogenicity studies of gB. Despite successes with other viral membrane fusion proteins, multiple studies on herpesvirus gB, including herpes simplex virus 1/2, and human cytomegalovirus, demonstrate that prefusion stabilisation does not increase neutralising antibody responses or improve vaccine efficacy. Factors such as glycan shielding, epitope masking, and structural subtlety between different conformations likely contribute to these outcomes. While for Epstein-Barr virus, there might be a trend towards improved B-cell neutralisation, gB from other herpesviruses is still to be tested. Beyond gB, other glycoproteins like gD and gH/gL complexes show promise as vaccine targets, with some eliciting more neutralising antibodies than gB. The review emphasises that alternative approaches, such as rational immunogen design, oligomerisation, optimised delivery systems, and adjuvants, may improve vaccine effectiveness. Finally, a comprehensive understanding of herpesvirus fusion on a mechanistic and structural level is crucial, as this allows innovative immunogen design, hopefully leading to the development of broad and durable herpesvirus vaccines.

Hijacked highways: plant virus modulation of vector proteins from entry to exit

2026-09-30

Arinder K Arora, Udvashika Puri, Kiran R Gadhave

Plant viruses rely on insect vectors to complete their transmission cycles, exploiting a diverse array of vector proteins to enable entry, intracellular movement, replication, and exit. This review synthesizes recent advances in our understanding of plant virus-vector protein interactions across noncirculative (NC) and circulative transmission modes, including vertical transmission. Key viral strategies include binding to surface proteins (e.g. Stylin-01, KRT), traversing epithelial barriers via receptor-mediated endocytosis (e.g. APN, ST6), trafficking through intracellular compartments (e.g. SNARE complexes, flotillin-2), and release through salivary exosomes. Some viruses hijack autophagy and apoptosis machinery to avoid degradation and ensure persistence. Others exploit reproductive proteins such as vitellogenin and sperm-specific serpin proteins - or even symbiont-derived membrane proteins - to achieve vertical transmission. In response, vectors activate immune pathways including RNA interference (RNAi), melanization, and mitogen-activated protein kinase signaling, although these defenses are frequently subverted by viral proteins. Mapping these molecular interactions highlights promising targets for intervention, including vector-targeted antibodies, RNAi-enabled symbionts, and receptor-blocking molecules. Together, these insights offer a path toward molecularly precise, ecologically sustainable strategies for disrupting plant virus transmission at the vector level.

DAMPs and adjuvant

2026-09-30

Minami Kojima, Daisuke Ori, Taro Kawai

Molecular mechanisms of NS2 pro activation in hepaciviruses and pestiviruses: regulation, intrinsic activity, and structural determinants

2026-09-30

Olaf Isken, Malte Morische, Norbert Tautz

Replication of all positive strand-RNA viruses depends on translation of a viral polyprotein, which is cleaved by viral and/or cellular proteases. The nonstructural protein 2 (NS2) of hepaciviruses and pestiviruses is responsible for NS2-NS3 cleavage, thus playing a highly specific and crucial role in viral polyprotein processing. Cleavage at the NS2/NS3 junction is essential for viral replication complex assembly and thus strictly regulated. Activation of hepaciviral and pestiviral NS2 cysteine proteases relies on different cofactors for optimal activity: while hepaciviral NS2 is reliant on the NS3 protease domain, classical pestiviral NS2 protease activation depends on the cellular chaperon DNAJC14. Despite its importance for the viral life cycle, how hepaci- and pestiviral NS2 protease activation is achieved remains ill-defined. Structural and functional data of hepaciviral NS2 protease revealed a dimeric composition with two composite active sites. Hepaciviral NS2 proteases harbor an intrinsic proteolytic activity that can be activated through specific surface residues. These surface residues are proposed to be pivotal for NS3-stimulated conformational changes in NS2. The activation mechanism for pestiviral NS2 protease is structurally less defined, but a cofactor-dependent, regulated NS2 pro activation is conserved for a large number of pestivirus species. This review will focus on recent insights into NS2 protease activation, with a focus on structural findings, host factor dependencies, and the conservation of proteolytic mechanisms among different members of the Flaviviridae family. Additionally, it will discuss perspectives on viral protein maturation, precursor function, and assembly of multiprotein complexes pivotal for the life cycle of these different viruses. • NS2-NS3 cleavage is pivotal for replication complex assembly. • NS2-NS3 cleavage is regulated by different activating cofactors. • HCV NS2 pro activation requires regulation by the NS3 pro domain. • HCV NS2 pro intrinsic activity can be stimulated via specific NS2 surface residues. • NS2 composite active-site and its activation are unique features of hepaciviruses .

Human genetic and immunological determinants of Epstein–Barr virus-driven disease

2026-09-30

Antoine Gondé, Benjamin Fournier, Sylvain Latour

Epstein–Barr virus (EBV) infects the vast majority of humans and establishes lifelong latency, yet causes disease in only a minority of individuals, underscoring the critical role of host determinants. This review examines the recent advances in how host genetics and immunological variation shape susceptibility to EBV across three major disease contexts. First, inborn errors of immunity have revealed essential CD8 + T-cell pathways governing control of EBV-driven B-cell lymphoproliferative disorders, through antigen recognition, co-stimulation, and cytokine signaling. EBV-positive T- and natural killer-cell lymphoproliferative disorders represent a second, more complex disease spectrum that arises through a multistep pathogenesis involving atypical viral entry, impaired immune control and homeostasis, and acquisition of somatic genetic alterations. Finally, we review new mechanistic evidence linking EBV to the development of autoimmune diseases, in particular multiple sclerosis and systemic lupus erythematosus, highlighting how EBV-mediated cell reprogramming amplifies immune dysregulation and self-reactivity. Together, these conditions establish EBV-associated diseases as powerful models for uncovering the complex genetic and immunological principles governing antiviral immunity and immune dysregulation.

Linking vector biology, transmission, and genome architecture in southeastern orthotospoviruses

2026-09-30

Abdelaal HA Shehata, Edward J Sikora, Amanda Strayer-Scherer, Kathleen M Martin

Targeting the virus–host interface for the development of therapeutics against filoviruses

2026-09-30

Juliette Dupré, Molly A Vickers, Allison Groseth, César Muñoz-Fontela, Thomas Hoenen

Until relatively recently, treatment for filovirus infections was limited to supportive care measures, but the occurrence of several large outbreaks in past years, including a multinational epidemic in West Africa from 2013 to 2016, has spurred the advancement of several therapeutic approaches into clinical trials, and even led to the recent licensure of two monoclonal antibody-based therapies against the Ebola virus. However, there are still significant gaps in our preparedness, in particular with respect to our ability to treat infections with other filoviruses, such as Marburg virus and Sudan virus. To address this, continuing research is focused on both leveraging what we have learned from these recent successes treating Ebola virus disease and exploring novel approaches for the management of filovirus infections. One promising approach toward the development of broad-spectrum therapeutics is focused on targeting the virus-host interface rather than directly targeting the virus itself. This review summarizes the currently licensed treatments, discusses current gaps, and highlights promising new directions in antiviral therapy both for EBOV and other filoviruses.

Architecture and evolution of viral complement evasion

2026-09-30

Hera Fatima, Abel Viejo-Borbolla, Thomas Krey

The complement system constitutes a powerful antiviral defense, centered on C3b-mediated amplification that drives opsonization, inflammation, and membrane attack complex formation. To persist in the eukaryotic host, viruses must neutralize this amplification step, and strikingly diverse evolutionary lineages have converged on inhibiting C3b-mediated amplification. In this review, we compare host and viral regulators of complement activation (RCAs) to reveal the structural and mechanistic principles underlying C3b control. Human RCAs achieve complement regulation through modular assemblies of complement control protein domains whose multivalency, linker-encoded geometry, and domain-specific dynamics enable efficient decay acceleration and factor I cofactor activity. Viruses have independently replicated these principles through distinct evolutionary routes. Poxviruses and gammaherpesviruses acquired host-derived RCA genes via horizontal gene transfer, followed by lineage-specific refinement on extensively different time scales. In contrast, alphaherpesviruses evolved structurally unrelated complement inhibitors, exemplified by glycoprotein C, which suppresses C3b via a binding interface distinct from that used by RCAs. Despite profound structural divergence, most viral strategies converge on inhibition of the C3b amplification loop. This convergence highlights C3b suppression as an evolutionary bottleneck imposed by complement and reveals a fundamental asymmetry between structural innovation and functional constraint. Understanding how viruses repeatedly solve this invariant problem identifies complement regulation as a durable vulnerability and suggests therapeutic strategies resilient to viral diversity and mutation-driven escape.

Editorial Overview: Immunopathogenesis in viral disease

2026-09-30

Suan-Sin Foo, Weiqiang Chen