We aimed to investigate the first Omicron cases detected in France in order to assess case characteristics and provide supporting information on the possible impact of this variant on the healthcare system. A standardized questionnaire was used to collect information from confirmed and probable Omicron cases. Median age of 468 investigated cases was 35 years, 376 were symptomatic (89%); 64% were vaccinated with two doses and 7% had received three doses. Loss of smell and taste were reported by 8.3% and 9% of cases, respectively. Seven cases were hospitalized, three of those were unvaccinated (including two with reported precondition). No admissions to intensive care and no deaths were reported. Our results confirm a mild clinical presentation among the first Omicron cases detected in France and highlight the importance for the national COVID-19 surveillance system to quickly detect and adapt to the emergence of a new variant.

Immune response against human cytomegalovirus (HCMV) includes a set of persistent cytotoxic NK and CD8 T cells devoted to eliminate infected cells and to prevent reactivation. CD8 T cells against HCMV antigens (pp65, IE1) presented by HLA class-I molecules are well characterized and they associate with efficient virus control. HLA-E-restricted CD8 T cells targeting HCMV UL40 signal peptides (HLA-E_UL40) have recently emerged as a non-conventional T-cell response also observed in some hosts. The occurrence, specificity and features of HLA-E_UL40 CD8 T-cell responses remain mostly unknown. Here, we detected and quantified these responses in blood samples from healthy blood donors (n = 25) and kidney transplant recipients (n = 121) and we investigated the biological determinants involved in their occurrence. Longitudinal and phenotype ex vivo analyses were performed in comparison to HLA-A*02/pp65-specific CD8 T cells. Using a set of 11 HLA-E/UL40 peptide tetramers we demonstrated the presence of HLA-E_UL40 CD8 αβT cells in up to 32% of seropositive HCMV⁺ hosts that may represent up to 38% of total circulating CD8 T-cells at a time point suggesting a strong expansion post-infection. Host’s HLA-A*02 allele, HLA-E *01:01/*01:03 genotype and sequence of the UL40 peptide from the infecting strain are major factors affecting the incidence of HLA-E_UL40 CD8 T cells. These cells are effector memory CD8 (CD45RA^highRO^low, CCR7^-, CD27^-, CD28^-) characterized by a low level of PD-1 expression. HLA-E_UL40 responses appear early post-infection and display a broad, unbiased, Vβ repertoire. Although induced in HCMV strain-dependent, UL40_15-23-specific manner, HLA-E_UL40 CD8 T cells are reactive toward a broader set of nonapeptides varying in 1–3 residues including most HLA-I signal peptides. Thus, HCMV induces strong and life-long lasting HLA-E_UL40 CD8 T cells with potential allogeneic or/and autologous reactivity that take place selectively in at least a third of infections according to virus strain and host HLA concordance. Understanding the mechanisms of immune control of viral infection is crucial to improve diagnosis and to design efficient immunotherapies. CD8 T lymphocytes are key components of the cellular immunity against human cytomegalovirus (HCMV), a widespread pathogen that cause severe illness and poor outcome in immunocompromised hosts such as transplant recipients and HIV-infected patients. In this study we characterized a population of non-conventional CD8 T lymphocytes directed against the viral protein UL40 and presented by the non-classical HLA-E molecules in blood samples from HCMV seropositive hosts. This immune response was detectable in around 30% of hosts, may represent up to 38% of total blood CD8 T lymphocytes, persists for life and thus seems to belong to the common immune arsenal against HCMV. Genetic factors related to the host and to the different strains of HCMV are critical parameters for the existence of this immune subset. Although specifically induced in response to HCMV infection, a key feature of these cells is their potential ability to be also responsive against multiple HLA molecules. In conclusion, HCMV infection frequently leads to the long-term persistence of a large subset of lymphocytes with potential side effect requiring attention in contexts such as autoimmunity and transplantation.

To investigate the relationship between neutralization escape and persistent high-level BK polyomavirus replication after kidney transplant (KTx), VP1 sequences were determined by Sanger and next-generation sequencing in longitudinal samples from KTx recipients with persistent high-level viruria (non-controllers) compared to patients who suppressed viruria (controllers). The infectivity and neutralization resistance of representative VP1 mutants were investigated using pseudotype viruses. In all patients, the virus population was initially dominated by wild-type VP1 sequences, then non-synonymous VP1 mutations accumulated over time in non-controllers. BC-loop mutations resulted in reduced infectivity in 293TT cells and conferred neutralization escape from cognate serum in five out of six non-controller patients studied. When taken as a group, non-controller sera were not more susceptible to neutralization escape than controller sera, so serological profiling cannot predict subsequent control of virus replication. However, at an individual level, in three non-controller patients the VP1 variants that emerged exploited specific “holes” in the patient’s humoral response. Persistent high-level BK polyomavirus replication in KTx recipients is therefore associated with the accumulation of VP1 mutations that can confer resistance to neutralization, implying that future BKPyV therapies involving IVIG or monoclonal antibodies may be more effective when used as preventive or pre-emptive, rather than curative, strategies.

Human polyomaviruses show relatively little genetic polymorphism between isolates, indicating that these viruses are genetically stable between hosts. However, it has become increasingly clear that intra-host molecular evolution is a feature of some polyomavirus (PyV) infections in humans. Mutations inducing premature stop codons in the early region of the integrated Merkel cell PyV genome lead to the expression of a truncated form of the large tumour (LT) antigen that is critical for the transformation of Merkel cell carcinoma (MCC) cells. Non-coding control region (NCCR) rearrangements and point mutations in virion protein (VP) 1 have been described in both JCPyV and BKPyV infections. In the context of JCPyV infection, molecular evolution at both these loci allows the virus to replicate effectively in the central nervous system, thereby leading to the development of progressive multifocal leukoencephalopathy (PML). In BKPyV infection, NCCR rearrangements have been linked to higher rates of virus replication in the kidney, and are proposed to play a direct causal role in the development of PyV-associated nephropathy. In all three of these infections, therefore, intra-host viral evolution appears to be an essential component of the disease process. This article is part of the theme issue ‘Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses’.

Hospital-acquired pneumonia (HAP) is one of the most common nosocomial infections, leading to significant morbidity and mortality in critically ill patients. HAP is previously associated with dysbiosis of the microbiota. However, the composition of the lung virome and its role in HAP pathogenesis remain unclear. Here, we longitudinally analyze the endotracheal virome in 87 critically ill patients, including 48 with HAP. Within the virome dominated by Caudoviricetes, a decrease in viral beta-diversity toward a bacteriophage-dominated signature and a distinct viral-bacterial interactome is observed 5-4 days before HAP onset. Lung virome composition, viral convergence before HAP onset, and conservation of 18% of the bacteriophage signature are validated in an external cohort of 40 patients. In silico causal inference further identifies bacteriophages associated with Streptococcus and Prevotella as a key regulator of HAP onset. These findings suggest an uncovered pathophysiological mechanism of HAP with virome involvement in lung microbiota dysbiosis. The discovery and validation studies are registered at ClinicalTrials.gov (NCT02003196 and NCT04793568).