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Human cytomegalovirus (HCMV) is a betaherpesvirus which rarely presents problems in healthy individuals, yet may result in severe morbidity in immunocompromised patients and in immune-naïve neonates. HCMV has a large 235 kb genome with a coding capacity of at least 165 open reading frames (ORFs). This large genome allows complex gene regulation resulting in different sets of transcripts during lytic and latent infection. While latent virus mainly resides within monocytes and CD34+ progenitor cells, reactivation to lytic infection is driven by differentiation towards terminally differentiated myeloid dendritic cells and macrophages. Consequently, it has been suggested that macrophages and dendritic cells contribute to viral spread in vivo. Thus far only limited knowledge is available on the expression of HCMV genes in terminally differentiated myeloid primary cells and whether or not the virus exhibits a different set of lytic genes in primary cells compared with lytic infection in NHDF fibroblasts. To address these questions, we used Illumina next generation sequencing to determine the HCMV transcriptome in macrophages and dendritic cells during lytic infection and compared it to the transcriptome in NHDF fibroblasts. Here, we demonstrate unique expression profiles in macrophages and dendritic cells which significantly differ from the transcriptome in fibroblasts mainly by modulating the expression of viral transcripts involved in immune modulation, cell tropism and viral spread. In a head to head comparison between macrophages and dendritic cells, we observed that factors involved in viral spread and virion composition are differentially regulated suggesting that the plasticity of the virion facilitates the infection of surrounding cells. Taken together, this study provides the full transcript expression analysis of lytic HCMV genes in monocyte-derived type 1 and type 2 macrophages as well as in monocyte-derived dendritic cells. Thereby underlining the potential of HCMV to adapt to or influence different cellular environments to promote its own survival.

Targeting interventions to areas that have recently experienced cases of disease is one strategy to contain outbreaks of infectious disease. Such case-area targeted interventions (CATI) have become an increasingly popular approach for dengue control but there is little evidence to suggest how precisely targeted or how recent cases need to be, to mount an effective response. The growing interest in the development of prophylactic and therapeutic drugs for dengue has also given new relevance for CATI strategies to interrupt transmission or deliver early treatment. Here we develop a patch-based mathematical model of spatial dengue spread and fit it to spatiotemporal datasets from Singapore. Simulations from this model suggest CATI strategies could be effective, particularly if used in lower density areas. To maximise effectiveness, increasing the size of the radius around an index case should be prioritised even if it results in delays in the intervention being applied. This is partially because large intervention radii ensure individuals receive multiple and regular rounds of drug dosing or vector control, and thus boost overall coverage. Given equivalent efficacy, CATIs using prophylactic drugs are predicted to be more effective than adult mosquito-killing vector control methods and may even offer the possibility of interrupting individual chains of transmission if rapidly deployed. CATI strategies quickly lose their effectiveness if baseline transmission increases or case detection rates fall. These results suggest CATI strategies can play an important role in dengue control but are likely to be most relevant for low transmission areas where high coverage of other non-reactive interventions already exists. Controlled field trials are needed to assess the field efficacy and practical constraints of large operational CATI strategies.

The membrane (M) protein of coronaviruses is essential for maintaining structural integrity during membrane virion budding and viral pathogenesis. Given its high conservation in lineages within the betacoronavirus genus, such as sarbecoviruses , the M protein presents as an attractive therapeutic target; however, developing broad-spectrum antivirals targeting coronaviruses such as MERS-CoV is challenging due to lower sequence conservation and limited structural information available beyond that of the SARS-CoV-2 M protein. In this study, we report 3-3.2 Å resolution structures of MERS-CoV M protein, engineered with a SARS-CoV-2-like antibody interface, representing the first human merbecovirus M protein structure, and SARS-CoV M protein structures, with and without a previously identified SARS-CoV-2 M protein inhibitor, JNJ-9676. We highlight the structural differences between the MERS-CoV, SARS-CoV and SARS-CoV-2 M proteins, and present insights into the conservation of the JNJ-9676 binding pocket as well as key differences that could be targeted to accelerate the design of specific MERS-CoV and broad-spectrum antivirals targeting coronavirus M proteins. Structural insights into SARS and MERS coronavirus membrane protein reveals differences and conserved sites of an inhibitor binding pocket, aiding in the design of broad-spectrum and specific antivirals.

Background: The evaluation of antiviral or vaccination strategies for the prevention of dengue infections in a traveler population would require extensive and complex studies. This prospective study aimed to identify a cohort of dengue naïve participants living in Medellín, a dengue endemic area, as a proxy for travelers and to determine the incidence of primary dengue virus (DENV) infection (symptomatic and asymptomatic) in this cohort. In Colombia, epidemic dengue waves occur every 3–4 years, with infected Aedes mosquitoes present in ~80% of the territory, including Medellín. Methods: Participants > 16 years of age, living in Medellín, were screened for anti-DENV immunoglobulin G (IgG). DENV seronegative participants were enrolled in this study. A serological anti-DENV survey was performed, with semiannual sample collections for up to 2 years. Acute DENV infections were evaluated by monitoring fever and testing for DENV nonstructural protein 1 and/or RNA. Results: Of the 4885 screened participants, 3008 participants (62%) were DENV seronegative and enrolled. Among them, 2263 (75%) completed this study, and 2644 (88%) had at least one serosurvey visit after baseline. Of those, 52 (2%) had laboratory-confirmed DENV seroconversion, and 19 (<1%) had febrile illness, but none had laboratory-confirmed DENV infection. Conclusions: This study identified a cohort of predominantly students, seronegative at study start, living in Medellín and serving as a proxy for a prospective DENV infection traveler population. Laboratory-confirmed primary DENV infection was found in 2% of participants, with <1% reporting febrile illnesses, meeting the WHO criteria for probable clinical dengue cases.

Abstract Dengue virus (DENV) causes repeated outbreaks of disease in endemic areas, with patterns of local transmission strongly influenced by seasonality, importation via human movement, immunity, and vector control efforts. An understanding of how each of these interacts to enable endemic transmission (continual circulation of local virus strains) is largely unknown. There are times of the year when no cases are reported, often for extended periods of time, perhaps wrongly implying the successful eradication of a local strain from that area. Individuals who presented at a clinic or hospital in four communes in Nha Trang, Vietnam, were initially tested for DENV antigen presence. Enrolled positive individuals then had their corresponding household members invited to participate, and those who enrolled were tested for DENV. The presence of viral nucleic acid in all samples was confirmed using quantitative polymerase chain reaction, and positive samples were then whole-genome sequenced using an amplicon and target enrichment library preparation techniques and Illumina MiSeq sequencing technology. Generated consensus genome sequences were then analysed using phylogenetic tree reconstruction to categorise sequences into clades with a common ancestor, enabling investigations of both viral clade persistence and introductions. Hypothetical introduction dates were additionally assessed using a molecular clock model that calculated the time to the most recent common ancestor (TMRCA). We obtained 511 DENV whole-genome sequences covering four serotypes and more than ten distinct viral clades. For five of these clades, we had sufficient data to show that the same viral lineage persisted for at least several months. We noted that some clades persisted longer than others during the sampling time, and by comparison with other published sequences from elsewhere in Vietnam and around the world, we saw that at least two different viral lineages were introduced into the population during the study period (April 2017–2019). Next, by inferring the TMRCA from the construction of molecular clock phylogenies, we predicted that two of the viral lineages had been present in the study population for over a decade. We observed five viral lineages co-circulating in Nha Trang from three DENV serotypes, with two likely to have remained as uninterrupted transmission chains for a decade. This suggests clade cryptic persistence in the area, even during periods of low reported incidence.

Dengue fever represents a significant medical and socio-economic burden in (sub)tropical regions, yet antivirals for treatment or prophylaxis are lacking. JNJ-A07 was described as highly active against the different genotypes within each serotype of the disease-causing dengue virus (DENV). Based on clustering of resistance mutations it has been assumed to target DENV non-structural protein 4B (NS4B). Using a photoaffinity labeling compound with high structural similarity to JNJ-A07, here we demonstrate binding to NS4B and its precursor NS4A-2K-NS4B. Consistently, we report recruitment of the compound to intracellular sites enriched for these proteins. We further specify the mechanism-of-action of JNJ-A07, which has virtually no effect on viral polyprotein cleavage, but targets the interaction between the NS2B/NS3 protease/helicase complex and the NS4A-2K-NS4B cleavage intermediate. This interaction is functionally linked to de novo formation of vesicle packets (VPs), the sites of DENV RNA replication. JNJ-A07 blocks VPs biogenesis with little effect on established ones. A similar mechanism-of-action was found for another NS4B inhibitor, NITD-688. In summary, we unravel the antiviral mechanism of these NS4B-targeting molecules and show how DENV employs a short-lived cleavage intermediate to carry out an early step of the viral life cycle. JNJ-A07 is a highly potent pan-serotype dengue virus inhibitor but the mechanism is not fully understood. Here, the authors show that JNJ-A07 blocks interaction between the viral protease/helicase complex NS2B/NS3 and the viral NS4A-2K-NS4B precursor, which then prevents formation of membranous replication organelles.

In this phase 2a, randomized trial, oral treatment with high-dose mosnodenvir, a pan–DENV serotype antiviral drug, led to a significantly lower DENV-3 RNA load than placebo after challenge in a controlled human infection model.

Coronaviruses are enveloped RNA viruses from the family Coronaviridae , notable for their crown-like spike glycoproteins. Though historically regarded as inconsequential, recent outbreaks, most notably COVID-19 caused by SARS-CoV-2, highlight their significant impact on global health. SARS-CoV-2 possesses a 27-31 kb, complex genome encoding multiple structural and non-structural proteins. The membrane/matrix (M) glycoprotein is the most abundant structural component of the viral envelope and confers the minimal requirement for virion formation. Its highly conserved structure, featuring three transmembrane domains, facilitates interactions with other viral proteins that are essential for assembly, budding, and maintaining the integrity of the viral envelope. Beyond its canonical functions in virion assembly and egress, emerging evidence suggests the M protein influences early infection processes, modulates host immune responses, and may serve as a promising antiviral target. This mini review consolidates current knowledge on the structure, multifunctional roles, and therapeutic potential of the coronavirus M protein, emphasizing the necessity for further research into its diverse functions throughout the viral lifecycle.

Prophylactic drugs against dengue are currently under development. In this study, we explored how such prophylactic approaches might affect dengue cases in four communes of Nha Trang City, Vietnam. A community level dengue transmission survey indicated high levels of previous exposure to dengue (89.7%; 95% CI: 87.2,92.0). We fitted a spatially explicit model to an observed outbreak and simulated likely effectiveness of Case-Area Targeted Interventions (CATI) and One-Time Mass Distribution (OTMD) of drug and vector control strategies. Increasing radius and effectiveness and decreasing delay of CATI was most effective, with drugs being more effective in averting dengue cases than vector control. Using an OTMD approach early in the outbreak required the least number of treatments to avert a case, suggesting that OTMD strategies should be considered as pre-emptive rather than reactive strategies. These findings show that pre-emptive interventions can substantially reduce the burden of dengue outbreaks in endemic settings.

Plasmid DNA (pcDNA1::MOMP) expressing the major outer membrane protein (MOMP) of an avian Chlamydophila psittaci serovar D strain and recombinant MOMP (rMOMP) with or without the immunomodulating CpG oligonucleotides (CpG ON) were tested for their ability to elicit an immune response and to induce protection in turkeys against homologous challenge. Two CpG ON were chosen for in vivo application based on their in vitro capacity to stimulate the production of nitric oxide (NO) in chicken macrophages and their in vitro capacity to induce turkey lymphocyte proliferation. Priming and boosting of turkeys with pcDNA1::MOMP was able to prevent severe clinical signs and bacterial replication in a turkey model of C. psittaci infection. rMOMP boosting induced high antibody titers, but these did not correlate with the level of protection. Although the CpG ON induced a significant in vitro response, the presence of the CpG ON as an adjuvant generated no significant effect on the immune response or on the protective capacity of the tested vaccination methods.