Sébastien Lhomme

BACKGROUND: Enteroviruses (EV)-A71 and EV-D68 are potentially associated with severe clinical conditions, especially in infants and young children. Population susceptibility to these viruses is unknown in France. AIM: We sought to estimate seroprevalence of EV-A71 and EV-D68 neutralising antibodies (nAbs) among children and adolescents living in France. METHODS: A stratified sampling approach based on sex, age and geographical area of residence was applied to obtain sera for routine diagnostic from ˂ 18-year-olds in metropolitan France. A total of 501 serum samples collected between 2023 and 2025 from 0–17-year-olds were included in the investigation. Neutralising activity was tested against EV-A71 sub-genogroup C1 and EV-D68 subclade B3 strains isolated in 2016, allowing to determine seropositivity and nAb titre. Data were analysed overall, by sex, age group and geographical area. RESULTS: For EV-A71, the overall estimated seroprevalence was 43.7% (95% CI: 39.3−48.2) while for EV-D68 this reached 96.0% (95% CI: 93.9–97.5). No differences according to sex were observed. Unlike EV-D68, EV-A71 seropositivity rate varied significantly by age group (p = 0.002) and area of residence (p < 0.001). Notably, 23 of 25 children aged ˂ 1 year lacked EV-A71 protective antibodies. Concerning nAb titres, significant differences occurred across age groups both for EV-A71 (p = 0.004) and EV-D68 (p < 0.001). The nAb titres appeared as highest in 1 to under-2-year-olds for EV-A71 and 0 to under-1-year-olds for EV-D68. CONCLUSION: This seroprevalence study in France reveals a high proportion of newborns and infants susceptible to EV-A71 at potential risk of severe disease, contrasting with the high level of immunity against EV-D68 across all paediatric age groups.

The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide. HEV infection can become chronic in immunocompromised individuals, in whom virus–host recombinant variants (VHRVs) can be detected. These variants often harbor host-derived insertions in the polyproline-rich region (PPR), and most display enhanced replication in vitro . However, the mechanisms underlying this replicative advantage remain unclear. It is likely that genes of the infected cells are differentially expressed according to the replicative capacity of the strain. The host factors involved in the improvement of the replicative capacity of these VHRVs are yet to be identified. In this study, we analyzed the host transcriptional response to seven VHRVs in HepG2/C3A cells using bulk RNA sequencing at 48 h and 168 h post-infection. Five VHRVs (RNF19A, ZNF787, KIF1B, RPS17, EEF1A1) previously associated with a high replication rate induced more significant, distinct transcriptomic changes than low-replicative variants (RNA18, RPL6), particularly at 168 h. A shared set of 25 genes, especially interferon-stimulated genes (ISGs), was upregulated in cells infected with high-replicating variants. Interestingly, ISG induction was limited at 48 h despite high viral RNA concentrations, suggesting a delayed antiviral response. At 168 h, high ISG expression coincided with high viral loads, indicating that VHRVs may evade or exploit immune defenses. Our findings reveal candidate ISGs such as IFIT1 and ISG15 that may influence HEV persistence and immune escape. These results offer new insights into the interplay between VHRV replication and host immunity. IMPORTANCE: Hepatitis E virus (HEV) is a major cause of acute hepatitis and can cause chronic infections in immunocompromised individuals. Virus–host recombinant variants (VHRVs) having integrated host-derived insertions often replicate more effectively, yet the host determinants of this phenotype remain unclear. With RNA sequencing of HepG2/C3A-infected cells, we observed that high-replicating VHRVs induce a delayed but strong expression of interferon-stimulated genes (ISGs), including IFIT1 and ISG15, despite high viral loads. These results suggest that VHRVs may transiently modulate or evade aspects of host antiviral defenses. Our study revealed host transcriptional patterns associated with enhanced viral replication, providing insight into potential mechanisms that enhance HEV replication and highlighting candidate pathways that could influence the interplay between viral replication and immune responses, all requiring further investigation.

Context: Bispecific antibodies (bsAbs) recently reshaped the treatment landscape of multiple myeloma (MM). Rare cases of progressive multifocal leukoencephalopathy (PML) have been reported in MM patients, and more recently in bsAbs-treated patients. Objectives: We aimed to investigate a potential safety signal for PML in patients with MM treated with bsAbs. Methods: We included all patients with MM treated with bsAbs identified in the French prospective registry of JC polyomavirus infections of the central nervous system and/or from the French pharmacovigilance database (FPVD). We also performed a systematic review. We then assessed whether a disproportionality signal for PML reporting exists, comparing bsAbs and other MM therapies in VigiBase®, the world pharmacovigilance database. Results: In the registry-FPVD cohort, 14 patients were included; all had at least triple-refractory MM, with a median disease duration of 13 years (IQR, 10-14) and were exposed to BCMA-targeting bsAbs (median time to PML diagnosis: 22 months, IQR, 12-24); 10 (71%) were in complete response. Main clinical manifestations included motor deficit, cognitive impairment and visual symptoms (8/14 patients each, 57%). Twelve (86%) had died from PML by month 12. Similar features and outcomes were observed in the systematic review (n=14 cases). PML reporting was significantly higher with bsAbs than with other MM therapies (Reporting Odds Ratio 17.7; 95% CI, 12.1-26.1). Interpretation: PML may represent an emerging complication in patients with MM receiving bsAbs. Vigilant monitoring and rapid assessment of new neurological deficits are critical in this population.

Hepatitis E virus (HEV) is a major cause of acute hepatitis worldwide. We evaluated the performance of the fully automated HEV RNA assay (HEV ELITe MGB® Kit) using the ELITe InGenius instrument. The limit of detection was established in line with the WHO standard (genotype 3a) and genotype 3f and 3c clinical samples. Finally, the analytical performance of the HEV ELITe MGB® Kit was compared with the Altostar® HEV RNA assay by testing 292 plasma samples and 10 stool samples. The ELITe tool utilized 200 µL of plasma or stool suspension eluted in 100 µL. Linearity was verified from 2 × 10 ⁶ IU/mL to 2 × 10 ³ IU/mL. The limit of detection for HEV‐3a, HEV‐3c, and HEV‐3f samples ranged from 485 to 523 IU/mL. The qualitative results obtained with both assays were concordant for 276/292 samples (94.5%) and good correlation was observed between both results for positive samples ( ρ = 0.98, p < 0.001). Sixteen samples tested negative with the ELITe assay but were positive using the Altona test, with viral loads ranging from 0.3 to 2.99 log ₁₀ IU/mL. All HEV RNA were detected in stool samples with both methods. These results indicated a lack of sensitivity for the ELITe assay. A second protocol using 600 µL of sample eluted in 50 µL of solution was evaluated and presented a limit of detection of 69 IU/mL using the WHO standard. While the ELITe assay demonstrated good linearity and correlation with the AltoStar® assay, it struggled to detect low levels of HEV RNA. However, a new extraction protocol may help to overcome this drawback but needs further validation and changes in the package insert of the manufacturer.

JC Polyomavirus (JCPyV) is a non-enveloped virus with circular double stranded DNA responsible for the rare but fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). In its host, this virus exists in two different forms: one found in the periphery, named archetype, and another found in the central nervous system, named prototype. This form usually harbors recombinations in the non-coding control region (NCCR), a key region that contains sequences regulating viral replication and containing binding sites for cellular transcription factors. This form also contains mutations in the capsid protein, especially VP1. Due to the diversity of the JCPyV, a natural polymorphism also exists between the different genotypes. In this review, we aimed to summarize the main features of the archetype and prototype strains in order to facilitate the interpretation of sequence data that are increasingly generated by new sequencing technologies. This will also help to distinguish mutations associated with the natural polymorphism from those specific to the prototype form.

Hepatitis E virus, a single-stranded positive-sense RNA virus, is the causative agent of acute viral hepatitis in humans and can lead to chronic infection in immunocompromised individuals. In this setting, strains containing host genome insertions within the polyproline region (PPR) of the pORF1 polyprotein were characterized and shown to display an increased replication rate across all systems. Using in silico modeling of pORF1 across 25 strains, combined with molecular dynamics (MD) simulations, we explored the structural variations caused by these insertions to investigate potential mechanisms underlying the increased replication rate compared to wild-type (WT) strains. Our results showed that the insertions neither induced structural organization within the PPR nor altered its intrinsically disordered nature. MD simulations further demonstrated that the overall stability of pORF1 remained unchanged in strains with insertions compared to WT strains. On the other hand, MD analyses revealed that strains with insertions exhibited an increased number of hydrogen bonds between the PPR and two other domains of pORF1: the MetY domain and the RNA-dependent RNA polymerase (RdRp). The stability of the MetY domain of the strains in the presence of host insertion events was higher than in the WT strains. These additional hydrogen bonds could position the MetY domain and the RdRp closer together, potentially promoting more efficient viral RNA synthesis. Validation of this hypothesis will require experimental structural studies, as well as computational modeling of the proposed dodecameric pORF1 structure.

The sources and routes of HEV infections in industrialized countries are not fully defined. Occitanie in Southern France is an hyperendemic area but the relative extent of contaminated food and water consumption is unknown. We used validated assays to determine IgG and IgM seroprevalence among 3480 French blood donors living in Occitanie and compared the data with those obtained about twelve years ago. Epidemiological information was collected using a specific questionnaire. HEV IgG seroprevalence increased from 39.1% in 2011% to 47.8% in 2023. Unlike 12 years ago, the wastewater treatment method and tap water consumption were linked to HEV infection. Consumption of bottled water is now a risk factor for HEV infection. Overall IgM seroprevalence was 1.3%. The high prevalence of anti‐HEV IgG in Occitanie cannot be explained by eating habits alone. Water consumption and treatment also appear to be important factors of HEV infections in Southern France.

Importance: Reactivation of the JC polyomavirus in individuals with impaired immunity is most commonly associated with progressive multifocal leukoencephalopathy. We report a case of polyomavirus-related retinopathy, representing a potentially novel manifestation of JC polyomavirus infection.Objective: To describe a patient with common variable immunodeficiency who exhibited isolated unilateral retinopathy related to JC polyomavirus infection of the retinal ganglion cell layer.Design, Setting, and Participants: This case report describes a patient managed at a referral center in Toulouse, France, from June 2022 to March 2025 presenting with progressive decrease in visual acuity related to a right-sided unilateral retinopathy.Interventions: Anterior eye chamber paracentesis was performed for polymerase chain reaction (PCR) and shotgun metagenome sequencing, and a retinal biopsy was taken for diagnostic purposes. An intravitreal injection of cidofovir was administered as a therapeutic procedure.Main Outcomes and Measures: The primary outcome was identification of a potentially novel manifestation of JC polyomavirus infection.Results: A 52-year-old White male presented with isolated, right-sided unilateral progressive retinopathy. Shotgun metagenome sequencing and specific PCR on anterior chamber paracentesis identified JC polyomavirus DNA. A biopsy of the retina demonstrated JC polyomavirus infection of retinal ganglion cells in the ganglion cell layer. A diagnosis of late-onset common variable immunodeficiency complicated by JC polyomavirus–related retinopathy was made. The single intravitreal injection of cidofovir administered was associated with transient negativation of the JC polyomavirus DNA PCR, but resulted in severe cidofovir-related adverse events.Conclusions and Relevance: This case report extends the spectrum of clinical phenotypes associated with polyomavirus infection and raises the possibility that retinopathy may be an underappreciated complication in this setting. Testing for JC polyomavirus should be considered in immunocompromised patients presenting with retinopathy of unexplained etiology.