Background: Emerging evidence suggests that antiviral treatment targeting human cytomegalovirus (HCMV) may improve outcomes in patients with glioblastoma (GBM). In this study, we analyzed serological data from the placebo-controlled VIGAS1 trial (Eudra number 2006-002022-29), which assessed the effect of valganciclovir (VGCV) on GBM progression in 42 patients, for impact of VGCV in preventing HCMV reactivation. Methods: VIGAS1 patients had undergone radical surgery and were randomized to receive either VGCV (n = 22) or placebo (n = 20) alongside standard radiochemotherapy. Blood was prospectively collected at baseline and 3-, 12- and 24-week follow-up visits. GBM cell lines and a cytomegalovirus-infected murine brain cancer model were used to validate the clinical findings. Results: Over the 24-week study period, we found that HCMV reactivation, as inferred from IgM seropositivity, occurred in 58.3% of patients in the placebo group, whereas this was completely prevented in the VGCV-treated group except for one patient with no treatment compliance (p = 0.0005). HCMV reactivation was linked to early recurrence. IgG-positive patients treated with VGCV showed a significantly longer time to progression (TTP) than those receiving placebo (6.7 vs. 3.7 months, p = 0.0408). We found a significant association between higher steroid doses and enhanced reactivation in the placebo group. In vitro and murine studies confirmed that corticosteroids, combined with radiation therapy, enhanced cytomegalovirus reactivation, which was mitigated by antiviral treatment. Conclusions: These findings suggest that preventing HCMV reactivation with antiviral therapy may improve patient outcomes, especially in HCMV-seropositive GBM patients, and further support the hypothesis that HCMV is a tumor-promoting virus.

Human cytomegalovirus (HCMV), a ubiquitous DNA betaherpesvirus, is capable of persistent infection and immunomodulation, particularly in immunocompromised and elderly hosts. Emerging evidence links HCMV to neurodegenerative diseases through its multifaceted immunomodulatory effects. This review summarizes key viral architectures and mechanisms, epidemiological trends, and experimental data supporting HCMV's role in cognitive decline. We advocate for targeted antiviral strategies and vaccine development to clarify its contribution to neurodegeneration.

Sjögren's disease (SD) is a chronic autoimmune disease characterized by immune-mediated damage to salivary and lacrimal glands. This study aimed to explore the potential link between SD and human cytomegalovirus (HCMV), by analyzing presence of HCMV proteins in salivary gland tissue specimens and prevalence of HCMV-specific antibodies in serum samples from SD patients and controls. HCMV-immediate early (IE) and late proteins (LA and pp65) were highly abundant in tissue specimens from SD patients (88.9 %, 69.2 %, 45.8 %, respectively), and less abundant in patients with Sicca symptoms without SD (70.5 %, 20.0 %, 12.5 %, respectively). Samples in the SD group were also positive at higher scores for the HCMV proteins than Sicca symptom patients without SD. IgM prevalence was higher in SD patients than in healthy controls (32.1 % vs. 13.4 %, P = 0.04) and HCMV-IgG titers were higher (P < 0.0001). Understanding the potential role of HCMV in SD pathogenesis may contribute to advancements in disease prevention and treatment.

Glioblastoma is the most common and aggressive primary malignant brain tumour in adults, with limited treatment options despite years of research. Since the 2005 introduction of the current standard of care, hundreds of clinical trials have failed to deliver significant breakthroughs. In 2002, human cytomegalovirus (HCMV) was detected in 100% of glioblastoma tumours. Although its role in cancer remains debated, and HCMV is not classified as an oncovirus, numerous studies have reported high viral prevalence in glioblastoma. HCMV can induce all 10 'hallmarks of cancer' and has been shown to modify both tumour cell behaviour and the microenvironment, which may enhance tumour growth and promote immune evasion. The association between HCMV and poor glioblastoma prognosis has generated increasing interest in targeting the virus therapeutically. Our clinical studies suggest that adding antiviral treatment to standard care may improve survival in both primary and recurrent glioblastoma. Moreover, an mRNA-based HCMV pp65 dendritic cell vaccine has shown preliminary indications of a potential survival benefit in early phase studies. Future research should prioritize clarifying HCMV's role in glioblastoma and rigorously evaluating antiviral and immunotherapeutic strategies in randomized clinical trials.This article is part of the theme issue 'The indirect effects of cytomegalovirus infection: mechanisms and consequences'.

Background: Efforts to understand atherosclerosis, a major cause of ischemic heart disease, have linked several lifestyle factors to increased risk for developing cardiovascular disease. Some studies suggest that cytomegalovirus (CMV), a widely prevalent herpesvirus, is reactivated in atherosclerotic plaques and associated with higher cardiovascular mortality risk. We aimed to explore whether CMV seropositivity and CMV-IgG antibody levels correlate with relevant biomarkers in a cohort of patients with myocardial infarction (MI) and matched controls. Methods and results: We analyzed a dataset from 324 survivors of MI treated in Stockholm between 1996 and 2001. Blood samples collected three months after MI were used to measure protective Apo B100 autoantibodies, metabolic, and inflammatory biomarkers. CMV serology was performed on stored serum samples. Correlation analyses were conducted between biomarkers and CMV serostatus in 324 patients and age- and sex-matched controls. While CMV seroprevalence was equal, the CMV-IgG levels were higher in controls. Among various factors examined, CMV seropositive MI patients had elevated levels of plasminogen activator inhibitor-1 (PAI-1) and interleukin-6, along with lower levels of MMP-3, than CMV seronegative MI patients. CMV-IgG levels correlated positively with PAI-1 levels in patients. Although CMV seropositivity was associated with increased proinsulin levels, there was no correlation with diabetes diagnosis. Conclusions: Our findings suggest an enhanced inflammatory and prothrombotic state in CMV seropositive patients after MI. Notably, patients had lower levels of CMV IgG than controls.

Background: Immune therapies are emerging as a critical component of cancer treatment, capable of delivering durable and potentially curative responses. While CAR-T cell therapy has proven effective for hematological malignancies, it faces challenges in treating solid tumors due to tumor antigen heterogeneity, an immunosuppressive tumor microenvironment, and physical barriers hindering CAR-T cell infiltration. NK cells, particularly adaptive NK (aNK) cells, offer a promising alternative due to their ability to recognize and kill tumor cells without prior sensitization and their resistance to immunosuppressive environments. Purpose: The study investigates the role of cytokines, specifically IL-21 and IL-15, in enhancing aNK cell expansion and activation using peripheral blood mononuclear cells (PBMCs) from healthy donors and tumor-infiltrating lymphocytes (TILs) from glioblastoma (GBM) patients. Methods: Buffy coats and GBM TILs were collected from Karolinska Hospital. NK cells were isolated and expanded in vitro with IL-15 and IL-21 cytokines and feeder cells (K562 and K562E). Furthermore, tumor lysate was added in the cultures to boost memory responses in aNK cells. NK cell functionality, cytotoxicity, and phenotyping was assessed using flow cytometry and statistical analysis (t-test and two-way ANOVA) used to validate the results. Further animal model was used to validate the cytotoxicity capacities of these cells against GBM tumors using a zebrafish model. Results: IL-21 drives the expansion of aNK better than IL-15 controls, data shown in PBMCs and TILs derived from GBM patients and IPLA OVCA patients. Additionally, the use of tumor lysate as a booster for restimulation further amplifies the cytotoxic capacity of aNK cells against autologous tumors. The zebrafish model validates this method, by decreasing the tumor size in zebrafish animals after 3 days of injection. Conclusion: The results demonstrate that IL-21 is essential for the specific expansion of aNK cells, enhancing their aggressiveness towards tumor cells. Additionally, tumor lysate significantly increases the cytotoxic efficacy of aNK cells upon restimulation with the same tumor cells. These findings suggest that IL-21 plays a crucial role in the specific expansion and activation of aNK cells, enhancing their aggressiveness towards tumor cells. By optimizing the expansion protocol, this method aims to advance the clinical application of aNK cells in immunotherapies for solid tumors, offering a potential solution to the limitations faced by current CAR-T therapies. ### Competing Interest Statement The authors have declared no competing interest.

Introduction: Previous studies have reported a correlation between a high-grade CMV-infection and an unfavorable prognosis in glioblastoma (GB). Coversely, epilepsy has been associated with a more favorable outcome in GB patients. Despites epilepsy and CMV share similar molecular mechanisms in GB tumoral microenvironment, the correlation between Tumor-Related-Epilepsy (TRE) and CMVinfection remains unexplored. The aim of our study is to examine the correlation between the dregree of CMV infection and seizure types on the survival of TRE Adult-type-diffuse-glioma. To achieve this objective, we conducted a comprehensive literature review to assess our results regarding previous publications Methods: We conducted a retrospective-observational study on TRE Adult-type-diffuse-gliomas treated at a single center in Mexico from 2010 to 2018. Tumor tissue and cDNA were analyzed by immunochemistry (IHC) for CMV (IE and LA antigens) at the Karolinska Institute in Sweden, and RT-PCR for CMV-gB in Torreon Mexico, respectively. Bivariate analysis (X2-test) was performed to evaluate the association between subtypes of Adult-type-diffuse-glioma (IDH-mut grade 4 astrocytoma vs. IDH-wt glioblastoma) and the following variables: type of hemispheric involvement (mesial vs. neocortical involvement), degree of CMV infection (<25%vs. >25% infected-tumoral cells) and seizure types [Focal awareness, focal impaired awareness, and FBTCS]. Kaplan Meier and Cox analyses were performed to determine the risk, p < 0.05 was considered statistically significant. Results: Sixty patients with TRE Adult type diffuse gliomas were included (80% IDH-wt glioblastoma and 20% IDH-mut grade 4astrocytomas). The mean age was 61.5 SD ± 18.4, and 57% were male. Fifty percent of the patients presented with mesial involvement of the hemysphere. Seizure types included focal awareness (15%), focal impaired awareness (43.3%), and FBTCS (41.7%). Ninety percent of cases were treated with Levetiracetam and 33.3% presented Engel-IA postoperative seizure control. More than 90% of samples were positive for CMV-immunohistochemistry (IHC). However, all cDNA analyzed by RT-PCR return negative results. The median of overall survival (OS) was 15 months. High-grade CMV-IE infection (14 vs. 25 months, p<0.001), mesial involvement (12 vs. 18 months, p<0.001), and FBTCS were associated with worse OS (9 vs.18 months for non-FBTCS). Multivariate analysis demonstrated that high-grade CMV infection (HR = 3.689, p=0.002) and FBTCS (HR=7.007, p<0.001) were independent unfavorable survival factors. Conclusions: CMV induces a proinflammatory tumoral microenvironment that contributes to the developmet of epilepsy. Tumor progression could be associated not only with a higher degree of CMV infection but also to epileptogenesis, resulting in a seizure phenotype chracterized by FBTCS and poor survival outcomes. This study represents the first survival analysis in Latin America to include a representative sample of TRE Adult-type diffuse gliomas considering CMV-infection-degree and distinguishing features (such as FBTCS) that might have potential clinical relevance in this group of patients. Further prospective studies are required to validate these results.

OBJECTIVES:In countries with access to early antiretroviral treatment (ART), opportunistic infections caused by cytomegalovirus (CMV) in people living with HIV (PLWH) are becoming increasingly rare. As potential complications are severe, it is critical to remain aware of this important diagnosis. However, clinical characteristics and prognosis of CMV infection in PLWH in the era of modern ART have not been well described. METHODS:Here, we compiled the clinical presentation, management and outcome of CMV infection in PLWH treated at the infectious diseases clinic of Karolinska University Hospital during 2010-2020. RESULTS:We identified 51 cases of active CMV infection, based on detection of CMV-DNA, mainly diagnosed in patients with CD4 T-cell count <200 cells/μL (86%). Median time from HIV diagnosis to detection of CMV infection was 16 days. In 20 cases (39%), CMV infection was symptomatic with retinitis identified as a manifestation in 70% of cases. Symptomatic CMV infection was treated for 73 (20-313) days upon diagnosis, mostly using valganciclovir. One-year mortality was 22% and was associated with longer time to ART initiation from HIV diagnosis and with comorbidities, but not with CMV-DNA levels or CD4 count. Immune reconstitution was not significantly compromised in patients with symptomatic CMV, although CD4/8 ratio tended to be lower in patients with systemic CMV infection. CONCLUSIONS:Retinitis remains the most common manifestation of symptomatic CMV infection in PLWH. Recognizing CMV infection is important, especially in the management of 'late presenters'. Adequate duration of antiviral therapy and appropriate follow-up must be ensured to avoid complications.

Background: Human cytomegalovirus (HCMV) is increasingly suggested to be involved in human carcinogenesis and onco-modulation due to its ability to contribute to all hallmarks of cancer. Growing evidence demonstrates a link between HCMV infection and various malignancies, including breast cancer, which incidence and mortality are still on the rise. The etiology of breast cancer remains mostly unclear, leaving 80% of breast cancer cases considered to be sporadic. Identifying novel risk- and prognostic factors for improved breast cancer treatment and increased survival rates, were the objectives of this study. Methods: Automated immunohistochemical staining results for HCMV proteins in 109 breast tumors and lymph node metastasis were correlated with clinical follow-up data (>10 years). Statistical analyses for median Overall Survival (OS) were performed. Results: Survival analyses revealed shorter median OS for patients with HCMV-IE positive tumors of 118.4 months compared to 202.4 months for HCMV-IE negative tumors. A higher number of HCMV-LA positive cells in the tumors was also associated with a shorter OS in patients (146.2 months vs. 151.5 months). Conclusions: Our findings suggest a link between HCMV-infections and breast cancer prognosis, which paves the way for potential novel clinical intervention and targeted therapy that may prolong the overall survival of selected patients with breast cancer.

Background: Human cytomegalovirus (HCMV) has been detected in tissue samples from patients with glioblastoma but little is known about the systemic immunological response to HCMV in these patients. Objectives: To investigate the presence and clinical significance of HCMV antibodies levels in plasma samples obtained from patients with brain tumors. Materials and Methods: HCMV-specific IgG and IgM antibody levels were determined in 59 plasma samples collected from brain tumor patients included in a prospective study and in 114 healthy individuals. We examined if the levels of HCMV specific antibodies varied in patients with different brain tumor diagnoses compared to healthy individuals, and if antibody levels were predictive for survival time. Results: HCMV specific IgG antibodies were detected by ELISA in 80% and 89% of patients with GBM and astrocytoma grades II–III, respectively, in all samples (100%) from patients with secondary GBM and brain metastases, as well as in 80% of healthy donors (n = 114). All plasma samples were negative for HCMV-IgM. Patients with brain metastases who had higher plasma HCMV-IgG titers had longer survival times (p = 0.03). Conclusions: HCMV specific IgG titers were higher among all brain tumor patient groups compared with healthy donors, except for patients with secondary GBM. Higher HCMV specific IgG levels in patients with brain metastases but not in patients with primary brain tumors were associated with prolonged survival time.

Susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is highly variable and could be mediated by a cross-protective pre-immunity. We identified 14 cross-reactive peptides between SARS-CoV-2 and influenza A H1N1, H3N2, and human herpesvirus (HHV)-6A/B with potential relevance. The H1N1 peptide NGVEGF was identical to a peptide in the most critical receptor binding motif in SARS-CoV-2 spike protein that interacts with the angiotensin converting enzyme 2 receptor. About 62%-73% of COVID-19-negative blood donors in Stockholm had antibodies to this peptide in the early pre-vaccination phase of the pandemic. Seasonal flu vaccination enhanced neutralizing capacity to SARS-CoV-2 and T cell immunity to this peptide. Mathematical modeling taking the estimated pre-immunity levels to flu into account could fully predict pre-Omicron SARS-CoV-2 outbreaks in Stockholm and India. This cross-immunity provides mechanistic explanations to the epidemiological observation that influenza vaccination protected people against early SARS-CoV-2 infections and implies that flu-mediated cross-protective immunity significantly dampened the first SARS-CoV-2 outbreaks.

Colorectal cancer (CRC) is one of the most common and fatal types of cancer. Inflammation promotes CRC development, however, the underlying etiological factors are unknown. Human cytomegalovirus (HCMV), a virus that induces inflammation and other cancer hallmarks, has been detected in several types of malignancy, including CRC. The present study investigated whether HCMV infection was associated with expression of the pro-inflammatory enzymes 5-lipoxygenase (5-LO) and cyclooxygenase-2 (COX-2) and other molecular, genetic and clinicopathological CRC features. The present study assessed 146 individual paraffin-embedded CRC tissue microarray (TMA) cores already characterized for TP53 and KRAS mutations, microsatellite instability (MSI) status, Ki-67 index and EGFR by immunohistochemistry (IHC). The cores were further analyzed by IHC for the expression of two HCMV proteins (Immediate Early, IE and pp65) and the inflammatory markers 5-LO and COX-2. The CRC cell lines Caco-2 and LS-174T were infected with HCMV strain VR1814, treated with antiviral drug ganciclovir (GCV) and/or anti-inflammatory drug celecoxib (CCX) and analyzed by reverse transcription-quantitative PCR and immunofluorescence for 5-LO, COX-2, IE and pp65 transcripts and proteins. HCMV IE and pp65 proteins were detected in similar to 90% of the CRC cases tested; this was correlated with COX-2, 5-LO and KI-67 expression, but not with EGFR immunostaining, TP53 and KRAS mutations or MSI status. In vitro, HCMV infection upregulated 5-LO and COX-2 transcript and proteins in both Caco-2 and LS-174T cells and enhanced cell proliferation as determined by MTT assay. Treatment with GCV and CCX significantly decreased the transcript levels of COX-2, 5-LO, HCMV IE and pp65 in infected cells. HCMV was widely expressed in CRC and may promote inflammation and serve as a potential new target for CRC therapy.

IntroductionHuman cytomegalovirus (HCMV) reactivation causes complications in immunocompromised patients after hematopoietic stem cell transplantation (HSCT), significantly increasing morbidity and mortality. Adaptive Natural Killer (aNK) cells undergo a persistent reconfiguration in response to HCMV reactivation; however, the exact role of aNK cell memory in HCMV surveillance remains elusive.MethodsWe employed mass spectrometry and computational prediction approaches to identify HLA-E-restricted HCMV peptides that can elucidate aNK cell responses. We also used the K562 cell line transfected with HLA-E0*0103 for specific peptide binding and blocking assays. Subsequently, NK cells were cocultured with dendritic cells (DCs) loaded with each of the identified peptides to examine aNK and conventional (c)NK cell responses.ResultsHere, we discovered three unconventional HLA-E-restricted 15-mer peptides (SEVENVSVNVHNPTG, TSGSDSDEELVTTER, and DSDEELVTTERKTPR) derived from the HCMV pp65-protein that elicit aNK cell memory responses restricted to HCMV. aNK cells displayed memory responses towards HMCV-infected cells and HCMV-seropositive individuals when primed by DCs loaded with each of these peptides and predicted 9-mer versions. Blocking the interaction between HLA-E and the activation NKG2C receptor but not the inhibitory NKG2A receptor abolished these specific recall responses. Interestingly, compared to the HLA-E complex with the leader peptide VMAPRTLIL, HLA-E complexes formed with each of the three identified peptides significantly changed the surface electrostatic potential to highly negative. Furthermore, these peptides do not comprise the classical HLA-E-restriction motifs.DiscussionThese findings suggest a differential binding to NKG2C compared to HLA-E complexes with classical leader peptides that may result in the specific activation of aNK cells. We then designed six nonameric peptides based on the three discovered peptides that could elicit aNK cell memory responses to HCMV necessary for therapeutic inventions. The results provide novel insights into HLA-E-mediated signaling networks that mediate aNK cell recall responses and maximize their reactivity.

The unfolding of the COVID-19 pandemic has been very difficult to predict using mathematical models for infectious diseases. While it has been demonstrated that variations in susceptibility have a damping effect on key quantities such as the incidence peak, the herd-immunity threshold and the final size of the pandemic, this complex phenomenon is almost impossible to measure or quantify, and it remains unclear how to incorporate it for modeling and prediction. In this work we show that, from a modeling perspective, variability in susceptibility on an individual level is equivalent with a fraction θ of the population having an “artificial” sterilizing immunity. We also derive novel formulas for the herd-immunity threshold and the final size of the pandemic, and show that these values are substantially lower than predicted by the classical formulas, in the presence of variable susceptibility. In the particular case of SARS-CoV-2, there is by now undoubtedly variable susceptibility due to waning immunity from both vaccines and previous infections, and our findings may be used to greatly simplify models. If such variations were also present prior to the first wave, as indicated by a number of studies, these findings can help explain why the magnitude of the initial waves of SARS-CoV-2 was relatively low, compared to what one may have expected based on standard models.

Viral infections enhance cancer risk and threaten host genome integrity. Although human cytomegalovirus (HCMV) proteins have been detected in a wide spectrum of human malignancies and HCMV infections have been implicated in tumorigenesis, the underlying mechanisms remain poorly understood. Here, we employed a range of experimental approaches, including single-molecule DNA fiber analysis, and showed that infection by any of the four commonly used HCMV strains: AD169, Towne, TB40E or VR1814 induced replication stress (RS), as documented by host-cell replication fork asymmetry and formation of 53BP1 foci. The HCMV-evoked RS triggered an ensuing host DNA damage response (DDR) and chromosomal instability in both permissive and non-permissive human cells, the latter being particularly relevant in the context of tumorigenesis, as such cells can survive and proliferate after HCMV infection. The viral major immediate early enhancer and promoter (MIEP) that controls expression of the viral genes IE72 (IE-1) and IE86 (IE-2), contains transcription-factor binding sites shared by promoters of cellular stress-response genes. We found that DNA damaging insults, including those relevant for cancer therapy, enhanced IE72/86 expression. Thus, MIEP has been evolutionary shaped to exploit host DDR. Ectopically expressed IE72 and IE86 also induced RS and increased genomic instability. Of clinical relevance, we show that undergoing standard-of-care genotoxic radio-chemotherapy in patients with HCMV-positive glioblastomas correlated with elevated HCMV protein markers after tumor recurrence. Collectively, these results are consistent with our proposed concept of HCMV hijacking transcription-factor binding sites shared with host stress-response genes. We present a model to explain the potential oncomodulatory effects of HCMV infections through enhanced replication stress, subverted DNA damage response and induced genomic instability.

Breast cancer is the most common cancer type among women, and concerningly its prevalence is steadily increasing. Some breast cancers are hereditary, but most are sporadic with an unknown cause. Accumulated evidence over the past two decades implies a very high prevalence of cytomegalovirus (CMV) in breast cancer. Detection of CMV proteins, which signifies an ongoing infection, has been found in 90%-100% of breast, colon, prostate and ovarian cancer, in sarcomas and in neural derived cancers such as glioblastoma, neuroblastoma and medulloblastoma. CMV is also found in lymph node and distant metastases, but viral proteins are not detected in healthy tissues around the tumor. The question therefore arises - does this virus play a role in tumorigenesis or as a tumor promoting virus? CMV is a common virus infecting 60-90% of the human population and while most have an asymptomatic infection, the immune system is unable to eliminate this virus during primary infection. CMV therefore establishes a life-long latent infection, persisting mainly in myeloid lineage cells. Stress, such as inflammation or genotoxic damage stimulates CMV reactivation, and clinical reactivation and CMV disease are common among organ and stem cell transplanted patients and AIDS patients who are immunosuppressed and unable to control reactivated infection. CMV also resides in cells of the breast and reactivates in breast milk in over 90% of CMV seropositive breastfeeding mothers, which results in 30-40% CMV seropositivity among one year old children. In a recent issue of eBioMedicine, Nehme and colleagues present evidence that further strengthens a role for CMV in breast cancer.1Nehme Z Pasquereau S Haidar Ahmad S El Baba R Herbein G Polyploid giant cancer cells, EZH2 and Myc upregulation in mammary epithelial cells infected with high risk human cytomegalovirus.eBioMedicine. 2022; Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar Of high importance, they were able to isolate CMV strains from primary breast tumor specimens. The tumor-derived CMV strains exhibited a slow growing high-risk phenotype that could transform normal mammary epithelial cells (NMEC). Mechanistically, infection promoted the development of a polyploid giant cancer cells (PGCC), which exhibited enhanced expression of the oncogene MyC and downstream activation of enhancer of zeste homologue 2 (EZH2). EZH2 is a histone-lysine N methyl transferase that mediates transcriptional silencing, acting together with EED and SUZ12 in the catalytic subunit of polycomb repressive complex 2 (PRC2) to introduce repressive histone marks (H3K27me3), but can also methylate non-histone proteins such as STAT3 or RNAs. High EZH2 expression is prominent in the most aggressive breast cancer phenotype triple-negative breast cancer (TNBC),2Gao B Liu X Li Z Zhao L Pan Y. Overexpression of EZH2/NSD2 histone methyltransferase axis predicts poor prognosis and accelerates tumor progression in triple-negative breast cancer.Front Oncol. 2020; 10600514Google Scholar which also has the highest PGCC content among different breast cancer phenotypes. EZH2 is overexpressed in PGCCs, and both EZH2 expression and PGCC content are associated with poor outcome in cancer patients.3Yu Y Qi J Xiong J et al.Epigenetic co-deregulation of EZH2/TET1 is a senescence-countering, actionable vulnerability in triple-negative breast cancer.Theranostics. 2019; 9: 761-777Crossref PubMed Scopus (30) Google Scholar High expression of EZH2 is associated with aggressive features including high proliferative capacity, induced stemness and accelerated cancer cell growth and metastatic potential. TNBC also has the highest prevalence of CMV among different breast cancer types. CMV infection can induce MyC, promote stemness, and activate pro-EZH2 pathways. EZH2 regulated STAT3 activation can silence the has-mir200 family4Wang Y Guo W Li Z et al.Role of the EZH2/miR-200 axis in STAT3-mediated OSCC invasion.Int J Oncol. 2018; 52: 1149-1164PubMed Google Scholar; this miRNA family controls translation of the CMV IE86 mRNA that is essential for CMV replication and controls cell growth.5O'Connor CM Vanicek J Murphy EA Host microRNA regulation of human cytomegalovirus immediate early protein translation promotes viral latency.J Virol. 2014; 88: 5524-5532Crossref PubMed Scopus (72) Google Scholar As EZH2 is implied is cancer initiation, metastasis, drug resistance, cellular metabolism and to control immune functions, viral activation of the MyC/EZH2 axis could have several effects on virus replication and cellular fate. The current study builds on previous work by this group, where high-risk CMV strains that caused stemness and enhanced epithelial to mesenchymal (EMT) plasticity were shown to induce transformation of NMECs.6Kumar A Tripathy MK Pasquereau S et al.The human cytomegalovirus strain DB activates oncogenic pathways in mammary epithelial cells.EBioMedicine. 2018; 30: 167-183Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar,7Moussawi FA Kumar A Pasquereau S et al.The transcriptome of human mammary epithelial cells infected with the HCMV-DB strain displays oncogenic traits.Sci Rep. 2018; 8: 12574Crossref PubMed Scopus (22) Google Scholar Infection promoted development of aggressive triple negative breast tumors in NSG mice.6Kumar A Tripathy MK Pasquereau S et al.The human cytomegalovirus strain DB activates oncogenic pathways in mammary epithelial cells.EBioMedicine. 2018; 30: 167-183Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar,7Moussawi FA Kumar A Pasquereau S et al.The transcriptome of human mammary epithelial cells infected with the HCMV-DB strain displays oncogenic traits.Sci Rep. 2018; 8: 12574Crossref PubMed Scopus (22) Google Scholar But perhaps this only relates to certain CMV strains, as other investigators observed that CMV infection in vitro with the TB40/E strain induced a mesenchymal to epithelial (MET) rather than an EMT phenotype.8Oberstein A Shenk T. Cellular responses to human cytomegalovirus infection: induction of a mesenchymal-to-epithelial transition (MET) phenotype.Proc Natl Acad Sci USA. 2017; 114: E8244-E8E53Crossref PubMed Scopus (36) Google Scholar In the present study TB40/E infection showed neither enhanced MyC expression nor oncogenic traits in infected fibroblasts and HMECs, and virus infection did not support soft agar growth, while the high-risk strains did. The CMV IE enhancer exhibited enhanced H3K4Me3 chromatin marks, and viral replication was enhanced with EZH2 inhibitors. Thus, certain viral strains may via high MyC expression and induced EZH2 activation exhibit slow growth properties supporting replication without killing the host cell. Such chronic infections may lead to enhanced genetic instability, accumulation of mutations and alterations in cellular metabolism, which are essential for tumor initiation. If only certain CMV strains are tumor promoting, this would explain why most carriers of CMV do not develop cancer, while most patients with certain tumors concerningly are CMV positive. Such CMV strains urgently need to be characterized in further depth, as if they are tumor promoting, these could be added in cancer screening programs and carriers of such strains be eliminated as blood and organ donors. If some CMV strains can promote tumor aggressiveness and negatively impact on prognosis, this opens for new treatment possibilities and a hope to improve patient outcome in those with CMV positive tumors. We have treated 139 glioblastoma patients with anti-CMV therapy and observed remarkably high extended survival in both primary and recurrent glioblastoma patients treated with antiviral drugs. Other colleagues observed extended survival of glioblastoma patients with CMV targeted immunotherapy approaches. Furthermore, the link between radiation therapy-induced CMV reactivation and potential rapid tumor recurrence provides further evidence of a role of CMV as a tumor promoter9Goerig NL Frey B Korn K et al.Frequent occurrence of therapeutically reversible CMV-associated encephalopathy during radiotherapy of the brain.Neuro Oncol. 2016; 18: 1664-1672Crossref PubMed Scopus (15) Google Scholar,10Merchut-Maya JM Bartek Jr., J Bartkova J et al.Human cytomegalovirus hijacks host stress response fueling replication stress and genome instability.Cell Death Differ. 2022; Crossref PubMed Scopus (2) Google Scholar and should be taken seriously, as it may be preventable. Indeed, Nehme and colleagues have taken an important step by isolating CMV from breast cancer specimens and identifying a viral link to MyC/EZH2 and PGCC, shedding light on an important pathway potentially explaining why only certain CMV strains may promote tumorigenesis and development of more aggressive tumors. Future studies should characterize the high-risk strains and further evaluate if tumor aggressiveness and recurrence can be reduced by protecting patients from CMV reactivation with anti-viral or viral directed immunotherapy approaches. This study was financed by Swedish Medical Research Council ( 2017-05807 ).

It has been very difficult to predict the development of the COVID-19 pandemic based on mathematical models for the spread of infectious diseases, and due to major non-pharmacological interventions (NPIs), it is still unclear to what extent the models would have fit reality in a "do nothing" scenario. To shed light on this question, the case of Sweden during the time frame from autumn 2020 to spring 2021 is particularly interesting, since the NPIs were relatively minor and only marginally updated. We found that state of the art models are significantly overestimating the spread, unless we assume that social interactions significantly decrease continuously throughout the time frame, in a way that does not correlate well with Google-mobility data nor updates to the NPIs or public holidays. This leads to the question of whether modern SEIR-type mathematical models are unsuitable for modeling the spread of SARS-CoV-2 in the human population, or whether some particular feature of SARS-CoV-2 dampened the spread. We show that, by assuming a certain level of pre-immunity to SARS-CoV-2, we obtain an almost perfect data-fit, and discuss what factors could cause pre-immunity in the mathematical models. In this scenario, a form of herd-immunity under the given restrictions was reached twice (first against the Wuhan-strain and then against the alpha-strain), and the ultimate decline in cases was due to depletion of susceptibles rather than the vaccination campaign.

Glioblastoma invariably recurs despite aggressive and multimodal first-line treatment and no standardized second-line therapy exists. We previously reported that treatment with the antiviral drug valganciclovir as an add-on to standard therapy significantly prolonged overall survival in 102 patients with newly diagnosed glioblastoma compared to contemporary controls. Here we present the results of retrospective survival analyses including patients with glioblastoma that initiated valganciclovir therapy after recurrence. Twenty-nine patients with recurrent glioblastoma received valganciclovir as an add-on to second-line therapy at Karolinska University Hospital. Contemporary controls were 109 patients with glioblastoma who received similar second-line therapy at our institution. We retrospectively analyzed survival data of these patients. Patients with recurrent glioblastoma who received valganciclovir had longer median overall survival after recurrence than controls (12.1 vs. 7.4 months, respectively, p = 0.0028). The drug was well tolerated. Both patients who underwent re-operation and patients that were not re-operated after recurrence benefitted significantly from valganciclovir therapy. Valganciclovir prolonged survival after recurrence both in patients with an unmethylated and methylated MGMT promoter gene. Valganciclovir was safe to use and prolonged median survival after recurrence for patients with recurrent glioblastoma, re-operated or not after recurrence, and with methylated or unmethylated MGMT promoter gene.

Phosphatidylinositol 3-kinase catalytic subunit p110β is involved in tumorigenesis and hemostasis. However, it remains unclear if p110β also regulates platelet-mediated immune responses, which could have important consequences for immune modulation during anti-cancer treatment with p110β inhibitors. Thus, we investigate how platelet p110β affects inflammation and infection. Using a mouse model of Streptococcus pneumoniae-induced pneumonia, we find that both platelet-specific p110β deficiency and pharmacologic inhibition of p110β with TGX-221 exacerbate disease pathogenesis by preventing platelet-monocyte and neutrophil interactions, diminishing their infiltration and enhancing bacterial dissemination. Platelet p110β mediates neutrophil phagocytosis of S. pneumoniae in vitro and curtails bacteremia in vivo. Genetic deficiency or inhibition of platelet p110β also impairs macrophage recruitment in an independent model of sterile peritonitis. Our results demonstrate that platelet p110β dysfunction exacerbates pulmonary infection by impeding leukocyte functions. Thereby, our findings provide important insights into the immunomodulatory potential of PI3K inhibitors in bacterial infection.

Human cytomegalovirus (HCMV) infection is an important cause of morbidity and mortality in immunocompromised patients and a major etiological factor for congenital birth defects in newborns. Ganciclovir and its pro-drug valganciclovir are the preferred drugs in use today for prophylaxis and treatment of viremic patients. Due to long treatment times, patients are at risk for developing viral resistance to ganciclovir and to other drugs with a similar mechanism of action. We earlier found that the endothelin receptor B (ETBR) is upregulated during HCMV infection and that it plays an important role in the life cycle of this virus. Here, we tested the hypothesis that ETBR blockade could be used in the treatment of HCMV infection. As HCMV infection is specific to humans, we tested our hypothesis in human cell types that are relevant for HCMV pathogenesis; i.e., endothelial cells, epithelial cells and fibroblasts. We infected these cells with HCMV and treated them with the ETBR specific antagonist BQ788 or ETR antagonists that are approved by the FDA for treatment of pulmonary hypertension; macitentan, its metabolite ACT-132577, bosentan and ambrisentan, and as an anti-viral control, we used ganciclovir or letermovir. At concentrations expected to be relevant in vivo, macitentan, ACT-132577 and BQ788 effectively inhibited productive infection of HCMV. Of importance, macitentan also inhibited productive infection of a ganciclovir-resistant HCMV isolate. Our results suggest that binding or signaling through ETBR is crucial for viral replication, and that selected ETBR blockers inhibit HCMV infection.