People living with HIV (PLWH) receiving HIV integrase strand transfer inhibitors (INSTIs) have been reported to experience virological failure (VF) in the absence of resistance mutations in integrase (IN). To elucidate INSTI resistance mechanisms and pathways, we performed long-term (1-2 years) passaging of lab-adapted and primary HIV-1 isolates in human T-cell lines and primary peripheral blood mononuclear cells with an escalating concentration of the INSTI dolutegravir (DTG). Independent of viral strain and cell type, HIV-1 acquired resistance to DTG through the sequential acquisition of mutations in Env and nucleocapsid (NC), with the occasional appearance of IN mutations. The Env mutations confer resistance to INSTIs by increasing the virus replication capacity through enhanced cell-cell transfer. In contrast, the NC mutations provide escape from INSTIs by accelerating the kinetics of viral DNA integration. The shortened time frame between the completion of reverse transcription and integration correlates with reduced sensitivity to DTG, suggesting that NC mutations limit the window of opportunity for INSTIs to bind intasomes and block integration. To assess the clinical relevance of results from our cell-culture selections, we analyzed samples from PLWH experiencing VF on a tenofovir-lamivudine-dolutegravir (TLD) regimen. Notably, plasma HIV RNA sequences from some individuals at VF showed NC mutations similar to those observed in vitro, with a subset also carrying IN mutations such as IN-R263K. Phenotypic analysis demonstrated that mutations in NC and IN act in concert to increase resistance to DTG. These results provide insights into the mechanism by which NC mutations reduce the susceptibility of HIV-1 to INSTIs and underscore the importance of genotypic analysis outside IN in individuals experiencing VF to INSTI-containing regimens.

Kaposi sarcoma herpesvirus (KSHV) drives multiple cancers including Kaposi sarcoma (KS). Pre-clinical animal models are needed to define virus-host interactions driving oncogenesis and to test novel therapies. We previously showed that KS skin implants in immunodeficient mice maintain KSHV-infected endothelial cells but remain confined to the implant borders. Here, we report that heterotypic implantation of KS from a patient with an anaplastic variant into a mouse kidney led to rapid tumor expansion that maintained LANA expression through six serial passages. This patient-derived xenograft (KS-PDX) recapitulates the atypical pathology of neoplastic non-spindled endothelial cells with a high mitotic index, matching the input biopsy. My collaborators discovered that key tumor suppressors and regulatory proteins are mutated in anaplastic KS, and spatial profiling revealed a dramatic transcriptional shift. Angiogenic and inflammatory pathways characteristic of conventional KS are downregulated, while pathways consistent with uncontrolled cell growth driven by host mutations are upregulated in anaplastic KS. Genomic instability extends to KSHV itself; sequencing reveals an unprecedented loss of two-thirds of the viral genome, leaving a truncated genome in the PDX identical to that found in patient tumor tissue with anaplastic pathology. Retained viral genes encompass the latency locus with known oncogenic properties, confirmed as expressed by RNAseq, while many genes essential to lytic replication and virion production are lost. In conclusion, my laboratory, working in collaboration with clinicians, computational scientists, and pathologists, has identified an aggressive anaplastic KS variant that is propogated as a PDX and recapitulates molecular and histopathological features of the patient's disease. This anaplastic KS-PDX model offers a unique opportunity to study the function of the retained viral genes expressed from a viral genome so destabilized that it is effectively locked in a self-perpetuating oncogenic state.

Epstein–Barr virus (EBV) establishes lifelong persistence in most humans and is traditionally described as alternating between latency and productive lytic replication. However, accumulating molecular and single-cell evidence indicates that EBV frequently occupies incomplete, abortive forms of lytic reactivation characterized by immediate-early/early (IE/E) gene expression without full viral DNA replication or virion production. The regulatory principles governing the stability of these states remain poorly understood.

Here, we propose a multi-scale nonlinear regulatory model in which EBV persistence emerges from threshold-dependent switching and feedback-controlled transitions between latent and lytic programs. We conceptualize latency and partial lytic reactivation as distinct attractor states separated by an activation threshold (T₁), while progression to productive replication requires crossing a higher replication threshold (T₂). In most physiological contexts, infected cells remain below T₂, forming a stabilized partial lytic attractor (IE/E expression, X<T₂). Positive feedback between IE/E expression, inflammatory signaling, and local immune modulation reinforces this state, whereas antiviral immunity (IFN signaling, NK/CD8⁺ responses) imposes negative constraints, generating hysteresis and dynamic equilibrium.

Rare transitions above T₂ initiate full lytic replication, leading to virion production and immune-mediated clearance. These transient events may nevertheless sustain infection at the population level by seeding newly infected B cells. The model further integrates therapeutic interventions, including replication inhibitors and “kick-and-kill” strategies, as modulators of threshold positioning and immune clearance efficiency.

This systems-oriented framework provides a mechanistic explanation for chronic immune activation, the frequent discordance between molecular markers of viral activity and detectable viremia, and the proposed associations between EBV and inflammatory or autoimmune conditions. By formalizing EBV reactivation as a nonlinear, feedback-regulated process, the model highlights replication thresholds as central determinants of viral persistence and potential therapeutic targets.

Climate change is fundamentally reshaping the landscape of infectious diseases by altering pathogen evolution, transmission dynamics, and host–vector interactions. Rising temperatures, extreme climatic events, and environmental disruption are expanding the geographic range of many pathogens, driving outbreaks in previously unaffected regions and revealing major limitations in existing surveillance systems. Integrated, genomics-driven surveillance frameworks provide a powerful approach to improve the detection, characterization, and anticipation of emerging and reemerging viral threats. Climate-linked factors—including increasing temperatures, flooding, droughts, and human displacement—are accelerating the spread of mosquito-borne and waterborne pathogens, creating conditions conducive to more frequent and severe epidemics. Applications of genomic epidemiology during major outbreak events, such as the emergence of Zika virus in Brazil, illustrate how high-resolution sequencing data can be leveraged to reconstruct transmission dynamics in real time. Recent advances in sequencing technologies, including amplicon-based long-read strategies, have further enabled rapid and scalable genomic surveillance of RNA viruses, particularly arboviruses. Beyond sequencing alone, the integration of genomic, epidemiological, ecological, mobility, and climate data supports phylodynamic and spatial modelling approaches capable of quantifying viral dispersal, identifying key drivers of transmission, and predicting areas at future risk under evolving climate scenarios. The application of these integrated systems in diverse real-world settings, including Europe and Africa, demonstrates how recent introductions and lineage expansions of dengue and chikungunya viruses reflect the combined effects of climate-driven range expansion and surveillance gaps. Collectively, these findings underscore the critical role of multidisciplinary, genomics-informed surveillance systems in strengthening global preparedness and guiding timely public health responses in the context of accelerating environmental change.

Neuronal latent infection of Herpes Simplex virus (HSV) is characterized by the association of the viral genome with repressive heterochromatin. Work for many groups has shown that histones associated with the latent genome have modifications indicative of different types of heterochromatin, including constitutive (H3K9me2/3) and facultative heterochromatin (H3K27me3). However, these subtypes of heterochromatin are largely understudied in terminally differentiated neurons. Further, hundreds of heterochromatin types exist, corresponding to different histone post-translational modifications and the reader proteins that bind them. Little is known about the histone reader proteins associated with the latent viral genome. A critical challenge in the field is neuronal heterogeneity, which likely drives divergent epigenetic outcomes and, consequently, varied reactivation potentials. Notably, the early host immune environment—specifically, exposure to type I or type II interferons during de novo infection—modulates the epigenetic structure of the viral genome and ultimately the reactivation capability. This indicates that neurons and the viral genome retain long-term molecular memory of prior immune stimulation, which ultimately determines reactivation potential. This talk will explore the role of specific heterochromatin-associated proteins in latency establishment, the different types of HSV-1 epigenetic structures that are more or less primed for reactivation, and how conditions during de novo infection, including exposure to interferons, have a long-term impact on the nature of HSV-1 latency and the ability of the virus to reactivate. Understanding the different types of heterochromatin that form on the latent genome is important for determining how latency is established and how heterochromatin is remodeled for reactivation. Ultimately, identifying epigenetic states that are less permissive to reactivation may facilitate the development of novel therapeutics to prevent reactivation.

Crimean-Congo Haemorrhagic Fever virus (CCHFv) is endemic in over 30 countries, primarily affecting Low- and Middle-Income Countries (LMICs) in Africa, the Balkans, the Middle East, and Asia, with an estimated 3 billion people at risk. The expanding geographic range of the tick host and the trade in infected but asymptomatic livestock are contributing to the spread of CCHFv. Unfortunately, there is currently no effective or recognised vaccine, and importantly, few recognised or commercial diagnostic assays for detecting and monitoring virus infection.

In our study, we developed and optimised a new diagnostic human IgG ELISA assay. We utilized flashBAC Ultra to optimise expression and purification of recombinant nucleoprotein (NP) from CCHFv using a novel insect cell line. From this we established protocols to produce high yields of CCHFv.NP antigen that minimised other contaminating proteins. The assay was developed to ensure that we used optimum antigen coating conditions, drying method, assay buffers and incubation times. Alongside, we have generated a novel positive antibody control for the assay using in silico humanisation from hybridomas isolated from CCHFv.NP-immunised mice.

The optimised assay was successfully used to screen a panel of serum samples identified as CCHFv-positive from Turkey, along with a wide range of negative serum samples.

As a result, we have produced a functional assay that is currently undergoing further evaluation in a range of laboratories, including plans for assessment in CCHFv endemic countries. Our aim is that this diagnostic ELISA for CCHFv exposure will be accessible to a broad range of laboratories, enabling them to conduct routine investigations, thus enhancing the efficiency of diagnosis and the subsequent management of infected patients. The ELISA will also be useful in screening patients for participation in future CCHFv vaccine trials and sero-surveillance studies to continue monitoring exposure to this important pathogen.

The viruses that infect bacteria, known as bacteriophages or phages, have evolved alongside a vast repertoire of bacterial defence systems that collectively define the microbial immune landscape. The enormous genetic diversity presented by phages raises a central question of how these systems detect the presence of an infecting phage. We discovered a class of bacterial defence proteins that sense the molecular choreography of viral assembly, detecting oligomeric intermediates of phage structural proteins to trigger abortive infection. Using biochemical, structural, and genetic approaches, we show that this mechanism couples real-time surveillance of phage virion assembly with rapid host self-sacrifice, effectively halting viral propagation. By targeting a conserved and obligate step in the phage life cycle, this strategy not only disrupts virion assembly but is also intrinsically resistant to escape mutations. This work expands the conceptual boundaries of antiphage defence recognition and highlights evolutionary convergence between bacterial and eukaryotic immune strategies that detect the molecular signatures of infection.

Antibodies neutralize viruses by inhibiting their entry into cells but a fraction of antibody-bound pathogens still escape into the cytosol. To counter this, every cell expresses TRIM21, a dedicated cytosolic antibody receptor and E3 ligase. TRIM21 intercepts incoming antibody-bound pathogens and targets them for ubiquitin-dependent degradation. Pathogens represent extremely challenging substrates yet TRIM21 is capable of eliminating them quickly before replication begins. TRIM21 contributes to immune protection against a remarkably broad range of pathogens, including enveloped and non-enveloped viruses and intracellular bacteria. In my talk I will discuss what we are learning about the different mechanisms TRIM21 uses against diverse pathogens and how TRIM21 synergises with the wider immune response. We are also attempting to apply our learnings to the development of new technologies and therapeutics. In the technology “Trim-Away”, TRIM21 provides an alternative to siRNA or CRISPR to remove specific proteins from the cell, whilst small molecule degraders that use TRIM21 - ‘TRIMTACs’ – offer the possibility of a new antiviral modality.

Flaviviruses and coronaviruses have repeatedly emerged as major human pathogens, causing outbreaks with significant public health, economic, and societal impacts. Their continued emergence and re-emergence underscore the urgent need to better understand the host-specific determinants that shape susceptibility to infection and disease severity. Our research focuses on dissecting virus–host interactions that govern viral replication and immune control, with particular emphasis on interferon-mediated innate immune responses. We investigate how differences in interferon signaling pathways influence cellular permissiveness to infection and determine the efficiency of viral replication and spread. In parallel, we study host dependency factors that are exploited by flaviviruses and coronaviruses throughout their replication cycles, from viral entry and genome replication to assembly and egress. Identifying these essential host factors provides critical insight into conserved mechanisms of viral replication and reveals potential targets for host-directed antiviral strategies. Together, these interdisciplinary efforts aim to define key determinants of viral emergence and pathogenesis, improve our ability to predict infection outcomes, and inform the development of effective antiviral interventions that are robust to viral evolution.

Viruses are obligatory intracellular microbes that exploit the host machinery to meet their biosynthetic demands. Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control. Along this direction, (i) we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical compound, ACA, was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo; (ii) utilizing influenza A virus (IAV) and SARS-CoV-2 as models, we demonstrated that both viral nucleoprotein (NP) harnessed host transcriptional corepressor TLE1 for enhancing viral polymerase activity while suppressing cellular innate response. NP-TLE1 recognition was realized via a conserved bHLH-like motif. Blockage of NP-TLE1 interaction by a peptide disruptor AH49A provides antiviral protection in vitro and in vivo. Our studies reveal evolutionarily conserved mechanism of host-virus interactions with broad relevance to human viral infections, which represents potential strategies for the development of antiviral agents.