Infection with dengue virus (DENV) is a major global public health threat, driven by mosquito transmission of four closely related virus serotypes. For effective transmission between hosts, DENV rapidly remodels the host cell to overcome multiple innate immune barriers and produce progeny virions. Here we review how DENV evades cell-intrinsic sensing and interferon (IFN) responses in both human and mosquito hosts. We highlight the roles of replication organelles, nonstructural proteins NS2B/3 and NS5, and subgenomic flaviviral RNAs in escaping RIG-I-like receptor and cGAS-STING signaling, disrupting JAK-STAT pathways, and subverting autophagy and ER-phagy. We further discuss NS1-mediated vascular leak, exploitation of TAM receptors, serotype-specific differences in IFN antagonism, and how these mechanisms might shape pathogenesis, host range, and epidemiological fitness. Finally, we consider how defined immune evasion strategies inform rational design of antivirals and next-generation live-attenuated tetravalent dengue vaccines to mitigate the escalating global dengue burden.
The evolution of dengue virus (DENV) is highly modulated by pathogen transmission bottlenecks and immunological pressures. These evolutionary events lead to mutations that cause antigenic changes and the replacement of DENV genotypes, which are directly correlated with epidemic magnitude and severe disease. India bears a disproportionately high dengue burden, accounting for nearly one-third of global cases, making it a persistent public health challenge. The periodic recurrence of outbreaks and cocirculation of all four serotypes pose challenges in disease control efforts. Nearly half of the country's population is seropositive for dengue, with varying seropositivity by age and geographical location. The spatiotemporal dynamics of prevalent serotypes in India are often associated with changes in transmission patterns, leading to cyclic outbreaks approximately every 2-3 years. Although multiple genotypes of serotypes have been recorded worldwide, Indian genotypes are highly diverged, with strong intermixing with neighboring countries. This review explores the mechanisms that drive DENV evolution underlying viral transmission bottlenecks, intrahost genetic diversity, and host immune responses. I also highlight the role of preexisting cross-reactive immunity and concurrent coinfections involving more than one serotype or other genetically similar arboviruses in the evolution of DENV. Finally, I outline the impact of DENV evolution on vaccine development and deployment in India.
Geminiviruses employ multifunctional protein ammunition to evade robust plant defense pathways. Key viral proteins effectively manipulate host signaling mechanisms to create a permissive environment for viral replication. Rapid evolutionary adaptation of geminiviruses, synergized by the proliferation of insect vectors, creates a challenge for effective disease control. Current plant resistance against geminiviruses primarily relies on antiviral RNA silencing and the localized cell death mechanism as an outcome of the hypersensitive response. To win the escalating arms race between geminivirus manipulation and subsequent plant counteracting strategies and effectively restrict viral invasion, these defense strategies need to be updated or supplemented with novel engineering approaches. In this review, we provide a critical contemporary understanding of viral reprogramming pathways and host counter-defense responses that provide new avenues to improve plant immunity against geminiviruses.
Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) remain among the most prevalent human pathogens, imposing a substantial global health burden. Recurrent orolabial and genital lesions affect millions worldwide, reflecting lifelong infection and the limited ability of current therapies to prevent reactivation and transmission. There have been no major therapeutic advances in over 40 years, and an effective vaccine remains elusive. New antivirals with novel mechanisms are needed, both to combat resistant strains and to enable combination therapies that reduce toxicity and potentially limit persistence. Recombination is a universal process essential for DNA replication, repair, and genome diversification. Increasing evidence indicates that HSV replication involves single-strand annealing (SSA) mediated by a conserved two-component recombination system composed of UL12, a 5'→3' exonuclease, and ICP8, the viral SSAP (single-strand annealing protein). Both UL12 nuclease activity and ICP8 DNA binding and annealing functions are required for productive infection, identifying them as promising targets for broad-spectrum antiviral development across human herpesviruses.
Eukaryotic cells compartmentalize critical biomolecular processes within membrane-bound organelles. Within these organelles, nucleic acids and proteins further compartmentalize into distinct structures known as membraneless organelles (MOs) via liquid-liquid phase separation. MOs enhance the specificity and rate of molecular processes by concentrating specific substrates, and their ability to quickly assemble and disassemble enables rapid regulation of molecular processes. RNA contributes to MO assembly and maintenance due to its ability to form a network of weak trans-molecular RNA-RNA interactions and multivalent RNA-protein interactions. Unsurprisingly, viruses have taken advantage of RNA condensation to enhance their replication and evade detection by host cells. However, recent studies have shown that several cellular antiviral sensors specifically activate on condensed viral RNAs. In this review, we discuss the intricate role of RNA condensation in viral replication and innate immune sensing and how host cells and viruses modulate these processes.
Viral-inspired materials (VIMs) integrate the nanoscale precision of viral architecture with the versatility of synthetic modification, enabling interfaces that bridge biological and technological systems. This review outlines how surface engineering governs the structure-function relationship of VIMs, highlighting six core design strategies: natural viral surface utilization, genetic and chemical decoration, hybrid composite formation, geometric and dimensional control, stimuli-responsive materials, and hierarchical assembly. These approaches expand the material and functional diversity of viral scaffolds across biomedical, catalytic, and electronic applications. Emerging trends include developing unconventional protein architectures, de novo protein design, and hybrid material creation. Together, these developments position VIMs as powerful platforms for dynamic, programmable, and multifunctional materials that integrate biological precision and synthetic design.
Insect vectors use a range of antiviral responses that influence their ability to acquire, replicate, and transmit human, animal, and plant viruses. Advances in comparative genomics, systems biology, transgenic tools, and single-cell profiling have identified both conserved immune frameworks and substantial divergence in antiviral strategies across vector and nonvector insects. This review examines the major antiviral pathways, including the RNA interference, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathways, as well as humoral and cellular responses, with a focus on recent findings that expand our understanding of virus-vector interactions. Evidence shows that viral recognition, downstream signaling, and the effects of individual pathways vary widely among vector species, tissues, virus families, and even individual viruses. By integrating cross-system comparisons, this review outlines emerging principles that govern antiviral responses in insect vectors and identifies key mechanistic gaps that limit current knowledge and the development of targeted transmission-blocking interventions.
Human influenza viruses demonstrate immense antigenic variability as a strategy to evade host immunity. The process of evolving to evade host antibody responses, known as antigenic drift, allows influenza viruses to evade epitope-specific antibodies, leading to seasonal influenza outbreaks. Neutralizing antibodies, the major drivers of antigenic drift, target a wide range of epitopes in hemagglutinin and neuraminidase, including functionally conserved regions. In this review, we describe antibody targets of influenza viruses, how influenza viruses have evolved to evade these antibody specificities, and how epistasis helps maintain viral fitness. Then we discuss emerging approaches to study and predict antigenic drift that may improve strain selection for seasonal influenza vaccines.
The existence of viruses as obligate intracellular parasites with high mutation rates sets them apart from other forms of life in fundamental ways. Frequent errors in replication and assembly processes give rise to substantial genetic and genomic diversity within viral populations. The diverse constituents of viral populations often interact within and across infected cells, giving rise to complex emergent phenotypes and genetic interactions. This review examines the causes and consequences of viral population diversity and explores how the complex collective interactions among viral genomes in cells and tissues blur the definition of individuality and influence patterns of viral replication and evolution across multiple biological scales.
The nuclear envelope protects the host genome, yet many viruses must breach this barrier to access nuclear replication machinery. The nuclear pore complex (NPC), the sole gateway for nucleocytoplasmic transport, is therefore a central target for viral nuclear entry. For decades, the mechanisms by which large viral genomes and subviral assemblies traverse this selective channel remained unclear. This was due to limited accessibility to intact nuclear pores, the NPC's massive architecture, and the transient nature of viral nuclear entry. The advent of cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET) has transformed this landscape, enabling visualization of NPC architecture and virus-NPC interactions at unprecedented detail. This review summarizes structural insights into NPC architecture and the strategies viruses employ to enter the nucleus. We examine how viruses engage canonical import pathways involving importins and phenylalanine-glycine-nucleoporins, as well as noncanonical mechanisms by which viral components mimic karyopherin. Finally, we offer perspectives on cryo-EM/cryo-ET capturing viral complexes during the entry process, revealing mechanisms of host-machinery exploitation by viruses.
Laboratory mice are widely used in biomedical research due to their low cost, genetic tractability, and ease of manipulation. To reduce experimental variability, they are typically housed under specific pathogen-free (SPF) conditions that limit microbial exposure. While this approach minimizes confounding infections, it also creates an immunological environment that differs markedly from that of humans, reducing the translational relevance of mouse immune studies. This limitation has driven the development of alternative models known as "dirty" or microbially experienced (ME) mice. Despite methodological differences, ME models demonstrate that lifelong microbial exposure profoundly shapes immune development. Although immune maturation in these mice is often attributed to microbiome changes, persistent exposure to endemic rodent viruses and other pathogens also may drive sustained immune activation. Here, we review the immune implications of the various ME models and highlight the critical role the virome plays in aligning mouse immune responses more closely with those of humans. Through harnessing microbial experience as a complementary tool to traditional SPF housing conditions and germ-free models, researchers can more faithfully model a mature, pathogen-shaped immune system.
In this article, I review highlights of my academic background and scientific journey in pursuit of understanding all things related to poliovirus and the molecular mechanisms that lead to an amazingly successful intracellular replication cycle. Although it is not possible to describe all my lab's research findings during the past five decades, I attempt to cover some of our major accomplishments and how they have influenced the field of virology as well as other areas of science.
Classification and nomenclature of viruses (i.e., virus taxonomy) are regulated by the International Committee on Taxonomy of Viruses (ICTV). Nomenclature aims for precise communication, and for that it is essential that names follow standard formats. In virus taxonomy, this is achieved with defined suffixes for each taxonomic rank. However, until recently, there was no standard format for the names of virus species. The use of Latinized (Linnaean) binomials for species names had been an objective of the ICTV since its creation, but for several reasons it had never been implemented. In 2021, after years of discussion and community consultation, the ICTV adopted a binomial format for virus species names, consisting of the genus name followed by a free-form species epithet. After a three-year transition period, all species names have now been converted to binomials. Virus names have not been changed, as they are not regulated by the ICTV.
The airway mucus barrier is both the first point of contact between respiratory viruses and the host and a frontline defense system that viruses must overcome prior to infection. Mucin glycoproteins within this barrier protect the underlying epithelium through trapping and clearance mechanisms and influence multiple aspects of viral pathogenesis including inflammation and transmission. Further, changes in mucin expression either associated with preexisting lung disease or induced during infection can affect disease severity. Research over the past century has aided our understanding of secreted and tethered mucin-mediated defenses and revealed insights into specific virus-mucin interactions and the effect of both physical virion attributes and viral glycoprotein function in facilitating mucus penetration. Here we discuss these advancements and highlight efforts to apply current knowledge to the development of mucin-inspired antiviral therapeutics. Still, given the diversity among respiratory viruses and complexity of mucin biology, open questions remain, indicating avenues for continued investigation.
A common cause of acute hepatitis in humans, hepatitis A virus (HAV) replicates within hepatocytes without inducing cytopathology. Virus is released from infected cells in the absence of cell lysis as quasi-enveloped HAV (eHAV) virions cloaked in host membranes. These virions circulate in blood when exported across the basolateral membrane of hepatocytes but are stripped of their membranes by bile salts when exported across the apical membrane into the biliary system resulting in fecal shedding of abundant naked, nonenveloped virus. This review summarizes the composition and structure of these two distinct types of infectious extracellular hepatovirus virions and outlines the evidence for specific signals within HAV capsid proteins that mediate interactions with the endosomal sorting complexes required for transport (ESCRT). Capsid protein interactions with the ESCRT-associated proteins ALIX and HD-PTP play a crucial role in the budding of newly assembled capsids into multivesicular endosomes, the first step in nonlytic release of quasi-enveloped virions from infected cells. This review also considers how eHAV virions enter naïve cells to establish infection in the absence of a virally encoded protein on their surface and compares the role played by quasi-envelopment in the hepatovirus life cycle with the nonlytic release of other types of viruses in extracellular vesicles.
Mitochondria play a vital role in cellular metabolism, energy production, and immune signaling, making them key targets for viral manipulation. Viruses exploit mitochondrial functions to enhance replication and evade immune responses. They also disrupt mitochondrial dynamics by altering fission/fusion balance and modulating mitophagy, which is essential for mitochondrial quality control. Additionally, they reprogram mitochondrial metabolism, affecting pathways such as oxidative phosphorylation and glycolysis to support replication. Viruses regulate apoptosis, either inhibiting or activating mitochondria-mediated apoptosis to prolong host cell survival or facilitate viral spread. Viral infections also induce oxidative stress through reactive oxygen species generation, affecting cellular integrity. Furthermore, viruses manipulate mitochondrial antiviral immunity by degrading mitochondrial antiviral signaling protein and triggering the release of mitochondrial DNA, modulating immune responses. Understanding these interactions offers valuable insights into viral pathogenesis and presents therapeutic opportunities. Targeting mitochondrial dysfunction and enhancing antiviral immunity could provide new strategies to mitigate viral damage and enhance cellular resilience.
Plant viruses, which can cause devastating plant diseases, are obligate intracellular pathogens that replicate their genomes inside cells and spread infection by cell-to-cell movement through cell wall nanochannels called plasmodesmata (PD). Double-stranded RNA, which occurs as a replication intermediate of RNA viruses, triggers adaptive and innate host defense responses that are controlled by virus-encoded effector proteins. These defenses include RNA silencing and RNA decay, which target viral RNA and inhibit virus accumulation, and pattern-triggered immunity (PTI), which targets PD and inhibits virus movement. This review discusses the role of RNA silencing, RNA decay, PTI, and effector-triggered immunity as antiviral defense mechanisms, how they are interrelated, and how viruses interact with these mechanisms to ensure their successful replication and spread throughout the plant organism.
My arrival into this world came quickly, according to my mother, and it feels like my life has mirrored that rapid beginning. I have enjoyed a rich, varied, and stimulating life and career that have gone through several phases. I credit genetics, my family, technological advances, and many environmental factors for shaping my career. Being a virologist allowed me to be curious and creative and to make several unexpected discoveries. This has been a fun and rewarding journey, but it wasn't always easy. I am not accustomed to talking about myself, but I am happy to share some scientific achievements and professional challenges with the hope that they illustrate the joy of research and the need for resilience and persistence to assure progress and acceptance of unexpected results.
Alphaviruses are mosquito-borne, enveloped viruses with a positive-sense, single-stranded RNA genome. Alphaviruses enter host cells via receptor-mediated endocytosis, using various cellular surface receptors such as matrix remodeling-associated protein 8 (MXRA8), low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3), and very low-density lipoprotein receptor (VLDLR), which facilitate binding to the viral glycoproteins. Following entry, viral proteins are expressed and nonstructural proteins assemble into replication complexes in host cells, driving RNA synthesis and genome replication. Viral assembly occurs at the plasma membrane, where nascent virions bud from the host cell in a process driven by capsid and spike proteins. Recent combinatorial structural studies have provided detailed molecular insights into various steps of the alphavirus life cycle. These structural insights into the alphavirus life cycle enhance our understanding of viral replication and assembly, with significant implications for antiviral strategies and the development of alphavirus-based vaccine vectors.
Bacteria have evolved a wide range of defense systems to combat phage infections. In the cheese industry, lactic acid bacteria (LAB) used for milk fermentation continuously face threats from phages. Therefore, selecting or developing industrial strains with enhanced phage resistance requires a focus on robust defense systems. Among these systems, the clustered regularly interspaced short palindromic repeats (CRISPR) and their CRISPR-associated proteins (Cas) are notably prevalent in LAB. The early characterization of this adaptive immune system was closely tied to the cheese industry, particularly with Streptococcus thermophilus in which CRISPR-Cas systems are ubiquitous and highly active. This review underscores the contributions of S. thermophilus and its virulent phages to our understanding of the function and mechanisms of CRISPR-Cas systems. Additionally, we review the diversity of CRISPR-Cas systems in LAB used in the cheese industry, the counter-defense strategies employed by dairy phages, and the applications of CRISPR-Cas systems within this sector.
