Search Results (325)

Herpesvirus infections belong to major pathogens in the human population. This study aimed at evaluating diagnostic data for eight human herpesviruses, based on datasets derived from a large European tertiary care center. Specifically, we analyzed 118,692 herpesvirus submittals to the Diagnostic Division of the Virological Institute, University Hospital Erlangen (UKER), Germany, between July 2014 and June 2024. Our points of focus were the following: (i) the frequencies of herpesvirus diagnostic results with positivity rates, (ii) departments representing main sample submitters, (iii) the specific importance of intensive care units (ICUs), (iv) the COVID-19 pandemic period, and (v) distinct properties of sample types. Overall, we are stating the highest frequencies of diagnostic assessment for herpes simplex virus (HSV), human cytomegalovirus (HCMV), and Epstein–Barr virus (EBV) infections, pointing to their dominant relevance for clinical practice. Notably, HCMV submittals (46.6% of total), together with EBV (26.2%) and HSV (15.7), accounted for almost 90% of all herpesviral diagnostic samples during this period. Within these key groups, HCMV, EBV and HSV showed positivity rates of 14.5%, 35.0%, and 18.5%, respectively. Concerning a main input of sample submittals, two departments were predominant in our center, i.e., the Departments of Haematology–Oncology and Anaesthesiology. These included patients under multifold types of treatment associated with an increased risk of herpesvirus reactivation or primary infection. Furthermore, another high portion of submittals was noted for ICUs and external sources. In addition, a numerical, transient increase in herpesvirus diagnostic submittals, from various sources, was shown for the COVID-19 pandemic years (mostly 2021) as compared to other periods. Combined, these data underlined the importance of clinical monitoring of herpesvirus infections, particularly for high-risk patients, and the steady need of improvements in preventive measures, therapeutic options, and safe diagnostic tools. Full article

Background: Previous work from our group demonstrated an association between immunohistochemical detection of Human cytomegalovirus (HCMV) late antigen and poor event-free survival (EFS) in pediatric medulloblastoma. Whole-genome sequencing (WGS) further identified increased abundance of HCMV-aligned reads at the UL88 locus, particularly in Group 3 tumors, a molecular subgroup associated with aggressive clinical behavior and poor prognosis. Methods: We performed an integrated multi-omics analysis of pediatric medulloblastoma using WGS (n = 39) and RNA sequencing (RNA-seq; n = 28) datasets. RNA-seq data were filtered using stringent alignment criteria (MAPQ ≥ 20) and compared with fetal brain (n = 12), adult brain (n = 12), and HCMV-infected cell culture controls (n = 3). Only high-confidence uniquely aligned reads were retained to reduce nonspecific and multi-mapped viral alignments. Sequencing reads were aligned to the HCMV Merlin reference genome (NC_006273.2) using a standardized analytical pipeline. A subset of 28 cases with matched tumor WGS, tumor RNA-seq, and germline WGS data was used for integrated multi-omics analyses. Orthogonal validation analyses were performed in Group 3 tumors using independent genomic and transcriptomic approaches. Exploratory survival analyses were conducted in a combined cohort (n = 84) integrating genomic and immunohistochemical datasets. Results: Recurrent low-level HCMV-aligned molecular signals were identified across medulloblastoma datasets. Reads aligning to UL76, UL88, and UL99 were the most consistently detected HCMV-associated late-gene signals across RNA-seq and WGS datasets. A composite HCMV late-gene signature (UL76–UL88–UL99) showed higher levels in Group 3 tumors than in other molecular subgroups (p < 0.05 in WGS analyses). Orthogonal analyses demonstrated concordant low-level HCMV-associated genomic and transcriptomic signals enriched in tumors with MYC-associated activation and chromosome 17 imbalance. In the combined cohort (n = 84), elevated HCMV-associated signal assessed by immunohistochemistry and genomic profiling was associated with reduced EFS (median 55 vs. 147 months; log-rank p < 0.001). The subgroup classified as HCMV-high Group 3 demonstrated the strongest association with adverse outcome in exploratory multivariable analyses (HR = 6.43, p = 0.002). Conclusions: This study identifies recurrent low-level HCMV-associated genomic and transcriptomic signals across pediatric medulloblastoma datasets, with preferential enrichment in biologically aggressive Group 3 tumors. Although the extremely low abundance of viral-aligned reads precludes definitive evidence of productive viral infection, the reproducible detection of HCMV-associated molecular signatures across independent sequencing platforms supports further investigation into a potential oncomodulatory association in pediatric medulloblastoma. Additional validation using optimized viral detection methodologies, independent cohorts, and mechanistic studies will be necessary to clarify the biological and clinical significance of these findings. Full article

Human cytomegalovirus (HCMV) remains an important medical problem in multiple patient settings despite the availability of antivirals. In part, this is linked to resistance, cost and restrictions on use in several patient settings. More generally, it remains attractive to increase our arsenal of anti-viral approaches to target HCMV. We previously characterized a potent inhibitor of HCMV infection, DIDS, that displays cysteine reactivity, allowing it to bind virions and neutralize HCMV infection of fibroblasts. We now show that DIDS is inhibitory to cell-free and cell-associated infection of multiple cell types, including cells of the haematopoietic lineage—cells important for latency and dissemination. Consistent with this broad activity, DIDS partially inhibited gB (but not SARS-CoV-2 spike) fusion activity. Intriguingly, further characterization of DIDS activity in myeloid cells revealed that, unlike in all other cell types, DIDS blocked a post-entry event in CD14+ monocytes and also dendritic cell derivatives. Despite viral entry, entry was largely silent, with a failure to activate innate immunity and cell survival pathways known to be activated by HCMV. In contrast, HCMV infection was observed to activate host miRNA expression in CD14+ cells, suggesting a DIDS-insensitive viral function was responsible or, alternatively, that host miRNA expression is a potential anti-viral response to viral internalization. Thus, we report the further characterization of a broad-acting inhibitor of HCMV infection, which may also prove a useful tool to study unique events for the infection of monocytic cells by HCMV—a cell type that is crucial for HCMV dissemination and pathogenesis in vivo. Full article

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. Full article

The mitogen-activated protein kinase (MAPK) pathways, ERK, JNK, and p38, are key regulators of immune responses during viral infections. These signaling cascades control cytokine production, T cell activity, and antigen presentation. However, many viruses can hijack MAPK pathways to avoid immune detection, promote their replication, and establish chronic infection. In this review, we discuss how different viruses, including HSV-1, HBV, HCMV, and SARS-CoV-2, manipulate MAPK signaling to alter host cell functions. A particular focus is given to the CD1d–iNKT cell axis, which plays a critical role in early antiviral responses but is often disrupted through MAPK-dependent mechanisms. We explore how changes in MAPK signaling affect antigen-presenting cells, drive T cell exhaustion, and reprogram immune cell metabolism, factors that contribute to viral immune evasion. The review also examines therapeutic strategies aimed at targeting MAPKs to improve antiviral immunity. These include small-molecule inhibitors and immune modulators that may enhance antiviral responses while limiting side effects. We emphasize the importance of context, as MAPK-targeted therapies must be carefully timed and tailored to avoid suppressing protective immunity or triggering unwanted inflammation. Overall, this review highlights the therapeutic potential and challenges of targeting MAPK pathways in viral infections and encourages further research into selective, host-directed antiviral strategies. Full article

Plastic pollutants, including phthalates, bisphenol A (BPA), per- and polyfluoroalkyl substances (PFAS), and microplastics (MPs), are increasingly recognized as emerging environmental cofactors that intersect with infectious disease dynamics. These compounds, once considered inert, can alter immune function, reshape host–pathogen interactions, and directly influence viral survival and transmission. In this review, we compile current evidence on the chemistry, environmental occurrence, and biological activity of major plastic-associated pollutants with emphasis on their role in viral infections. Phthalates such as di(2-ethylhexyl) phthalate (DEHP) and its metabolite MEHP modulate innate immune signaling and have been shown to exacerbate infections, including Dengue and Coxsackievirus B3. Other DEHP-like phthalates, such as dibutyl phthalate (DBP), exhibit consistent infection-enhancing effects, while high molecular weight or cyclical phthalates such as polyvinyl acetate phthalate (PVAP) display conflicting results in their modulation of viral infections. BPA, widely detected in human tissues, acts through endocrine and immune disruption, worsening viral myocarditis, and altering influenza outcomes. PFAS, persistent “forever chemicals,” reshape adaptive immune responses and are associated with increased susceptibility, viral persistence, or severity of infection of herpesvirus (HCMV, EBV, HSV-1), hepatitis virus, and influenza infection. Microplastics represent a distinct risk by acting as physical carriers for viruses and bacteria, stabilizing viral RNA, enhancing host cell uptake, and skewing immune responses. Together, these pollutants extend beyond toxicology into virology, providing novel insights into how environmental exposures converge with viral pathogenesis. We highlight mechanistic advances and critical knowledge gaps and propose future directions for integrating environmental health and infectious disease research. Full article

Human cytomegalovirus (HCMV) and Human Immunodeficiency Virus (HIV) are two pathogens known to have dramatic consequences when contracted early in life. In addition to having a significant impact when acquired individually, these two viruses are known to frequently cause coinfections. Indeed, also in the modern era, HCMV remains one of the most prevalent coinfections in newborns of mothers living with HIV, including both HIV-positive children regardless of their immune status, and those exposed to HIV but uninfected (HEU). In children with HIV infection, HCMV coinfection has historically been associated with AIDS-defining disease, high mortality, and prolonged, elevated HCMV viral load. Although timely administration of antiretroviral therapy prevents immunodeficiency in people living with HIV and thus reduces the incidence of full-blown HCMV disease in cases of coinfection, emerging data suggest that HCMV-induced immune activation and aging persist, potentially contributing to long-term, non-AIDS-related comorbidities. Growing evidence indicates that also HCMV amplifies HIV susceptibility, disease progression, and immune dysregulation through multiple synergistic mechanisms. Moreover, congenital and early postnatal HCMV infections occur at significantly higher rates in HEU newborns than in HIV-unexposed children and are associated with worse clinical outcomes, particularly when HCMV viral loads are high. This review summarizes current knowledge on the epidemiology, clinical impact, and immunopathogenetic interactions of early HCMV–HIV coinfection in pediatric populations. By integrating recent findings with historical evidence, it highlights critical mechanistic and epidemiological gaps that warrant further investigation. Full article

(1) Background: Sepsis is characterized by profound heterogeneity of immune responses, complicating biomarker-based prediction of clinical outcomes. Latent human cytomegalovirus (HCMV) infection is one of the strongest modulators of the human immune system and may influence cytokine-mediated signaling during sepsis. (2) Methods: In this post hoc analysis of 331 patients from the prospective multicenter SepsisDataNet.NRW cohort (German Clinical Trial Registry No. DRKS00018871), we quantified 13 serum cytokines on day 1 after sepsis diagnosis and determined HCMV IgG serostatus via ELISA. Using nested cross-validated logistic regression with exhaustive feature selection, we identified cytokine panels predictive of 30-day survival in the total cohort and in subgroups stratified by HCMV serostatus. (3) Results: In the total cohort, a four-cytokine panel (IL-6, IL-10, TNF-α, IL-12p70) predicted 30-day survival with a cross-validated area under the curve (AUC) of 0.66 [95% CI: 0.59–0.72]. Stratification by HCMV serostatus revealed distinct predictive profiles: in HCMV-seropositive patients, a two-cytokine model (IL-10, IL-23) achieved an AUC of 0.69 [95% CI: 0.61–0.77], whereas in seronegative patients, a model based on IL-8 and IL-17A failed to generalize (AUC = 0.47 [95% CI: 0.33–0.61]). Kaplan–Meier analysis confirmed a significant separation of survival curves for the HCMV-seropositive group (p < 0.001) but not for seronegative patients (p = 0.282). (4) Conclusions: HCMV serostatus defines an immunological context in which cytokine-based prediction of sepsis outcome becomes feasible. These data suggest that viral serostatus should be systematically incorporated into biomarker discovery and immunophenotyping approaches to improve the reproducibility and biological interpretability of sepsis endotyping. Full article

Human cytomegalovirus (HCMV) infection is a significant complication in transplant recipients. Following HCMV reactivation, the recovery of T-cell responses serves as a key indicator of protection from HCMV disease. This study aimed to assess the HCMV-specific CD4⁺ and CD8⁺ T-cell responses and their cytokine production (IFNγ, TNFα, IL2) against various HCMV proteins (IE-1, pp65, gB, gH/gL/pUL128L) in solid organ transplant recipients (SOTRs) and hematopoietic stem cell transplant recipients (HSCTRs) with active HCMV infection. The cohort consisted of 16 SOTR and 16 HSCTR categorized into two groups: (i) Controllers, who spontaneously controlled the infection, and (ii) Non-Controllers, who required antiviral treatment. T-cell responses were analyzed following stimulation with peptide pools and intracellular cytokine staining. Prior to transplantation, all patients exhibited a significantly higher frequency of CD4⁺ T cells specific to pp65 compared to gH and gL/pUL128L. During the peak of infection, T-cell frequencies across all peptides were similar, but at infection resolution, the frequency of pp65 and gB-specific CD4⁺IFNγ⁺ T cells was significantly higher than gL/pUL128L. Additionally, pp65 and IE-1-specific CD8⁺IFNγ⁺ T-cell responses were significantly greater than those against gH and gL/pUL128L at the resolution of infection. Notably, Controllers exhibited significantly higher frequencies of monofunctional pp65-specific T cells, particularly in CD8⁺ T cells producing IFNγ and TNFα. The response to pp65, especially IFNγ production, may serve as a key marker for identifying patients capable of controlling HCMV infection. Full article

The complex relationship between human cytomegalovirus (HCMV) and cancer has been of interest since the 1960s. As a highly prevalent human β-herpesvirus, HCMV establishes lifelong latency in CD34+ myeloid progenitor cells and has been implicated as an oncomodulatory virus in various cancers, including glioblastoma multiforme, breast, prostate, colorectal, and ovarian cancer (OC). Recently, discussions have emerged regarding the classification of HCMV as an eighth oncovirus due to the persistence of its nucleic acids and proteins in many tumour types. As one of the deadliest gynaecological cancers, OC is often characterised as the ‘silent killer’ with less than half of women surviving for 5 years, a rate that drops below 20% when detected at advanced stages. Reported effects of HCMV vary between cancers, likely due to differences in tumour type, viral strain, and disease stage. While HCMV infection has been linked to poor OC patient outcomes, its impact on the OC tumour microenvironment (TME) and immune system remains less understood. Investigating HCMV’s potential oncogenic role could provide critical insights into OC progression. This review discusses recent developments on HCMV’s multifaceted roles in OC, including strain heterogeneity, immunomodulation of the TME, dysregulation of inflammatory signalling pathways, and potential therapeutic approaches targeting HCMV in anti-cancer immunotherapies. Full article

Human cytomegalovirus (HCMV) is a herpesvirus (family) belonging to the beta herpesvirus subfamily that causes significant morbidity both in immunocompromised hosts (horizontal transmission) and during vertical transmission from mother to child. HCMV has the ability to establish a permanent latent infection with its host (even for decades), in which the DNA remains as a silent nuclear episome (latent phase) until reactivation after the appropriate conditions have occurred (lytic phase). The transition between the two phases (latent/lytic) is largely determined by the type of infected cell and the health status of the host, which ultimately corresponds to the epigenetic state of the infected cells. Lytic infection of the virus normally occurs in epithelial cells, endothelial cells, fibroblasts or macrophages, whereas the latent phase occurs when undifferentiated cells of the myeloid lineage, such as CD34+ hematopoietic progenitor cells, are infected. Epigenetic regulation of the viral genome begins with the formation of chromatin in the viral DNA just 30 min after infection and then evolves towards the latent or lytic phase. DNA viruses, including members of the herpesvirus family, are currently the subject of intense study regarding the role that epigenetics plays in controlling the viral life cycle, focusing primarily on the role of post-translational modifications (PTMs) of histones, as well as DNA methylation. Within the viral genome, nucleosomes are organized for the spatial/temporal expression of appropriate genes due to epigenetic modifications. Therefore, during the infection cycle, DNA chromatinization and chromatin modifications influence the expression of genes in the HCMV genome. This process is mediated by (i) enzymes called “writers”, which catalyze PTMs by adding chemical groups to proteins (acetylation, methylation, etc.); (ii) recruitment of specific transcription factors called “readers”, that bind to modified amino acid residues of proteins and act as interpreters of the PTM code; and (iii) “erasers”, enzymes that remove these modifications (e.g., HDACs). Indeed, recent advances in understanding the chromatin-based mechanisms of viral infections offer some promising strategies for therapeutic intervention that could be particularly useful in immunosuppressed recipients of transplants to avoid allograft rejection and infection by other opportunistic pathogens. In this review, we comprehensively examine the epigenetic regulation of the HCMV genome across distinct phases of viral infection, with particular attention to recent studies that significantly enriched the current knowledge about molecular mechanisms and future therapeutic perspectives. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations. Full article

Human cytomegalovirus (HCMV) is a complex pathogen that encodes a diverse array of proteins essential for its survival and replication within host organisms. Among these proteins, a noteworthy group comprises four chemokine-like G protein-coupled receptors (cellular GPCRs), which play pivotal roles in the virus’s evasion of the host immune response and the establishment of persistent infections. Of particular interest is pUS28, recognized as one of the most extensively studied viral GPCRs (vGPCRs). This receptor has attracted significant attention for its potential as a target for innovative antiviral therapies aimed at addressing HCMV-related diseases. In contrast, pUS27 has not been as thoroughly characterized, presenting a potentially promising avenue for antiviral intervention. The relative scarcity of research surrounding pUS27 underscores an exciting opportunity for further exploration, as a deeper understanding of its functions and mechanisms may reveal novel strategies for combating HCMV infections. This review seeks to synthesize recent advancements in our understanding of pUS27, elucidating its biological roles, interactions, and potential implications for therapeutic development. We will also highlight critical gaps in the existing literature that warrant further investigation, underscoring the need for a more comprehensive understanding of this understudied receptor. By delving into the complexities of pUS27, we aim to inspire future research initiatives that could lead to the development of novel antiviral treatments, thereby enhancing our overall understanding of HCMV pathogenesis. Importance: The study of vGPCRs is essential for understanding how viruses like HCMV manipulate host cell signaling and evade immune responses. While pUS28 has been extensively studied due to its broad chemokine binding and signaling activity, its lesser-known homolog, pUS27, warrants closer attention. Likely arising from a gene duplication event, pUS27 shares approximately 31% sequence identity with pUS28 and is conserved across HCMV strains, suggesting an important functional role. By focusing on pUS27, we may uncover shared mechanisms that allow therapies to effectively target both pUS28 and pUS27, potentially leading to more potent antiviral treatments. The implications of studying pUS27 are profound, as it could play a pivotal role in improving our approaches to combating HCMV and enhancing our overall understanding of immune evasion strategies. Full article

Congenital human cytomegalovirus (HCMV) infection is the most common vertically transmitted viral infection, and it affects 1 in 200 live births worldwide. While neonates are often asymptomatic at birth, congenital HCMV infection can result in long-term complications, including microcephaly, sensorineural hearing loss, and neurodevelopmental abnormalities. Developing antiviral strategies for the treatment and prevention of congenital HCMV infections is a global public health priority. However, licensed anti-HCMV vaccines are not yet available, and therapeutic options for use during pregnancy remain limited. The complement system is a crucial component of the innate immune system that plays essential roles in both fetal development and maternal defense against infectious pathogens. In cases of congenital HCMV infection, complement may contribute to the successful containment of the virus, but dysregulation and overactivation could concurrently drive tissue-damaging inflammation. This review discusses the known roles of the complement system in fetal development and in HCMV pathogenesis and synthesizes existing research to develop the hypothesis that a dysregulated complement system is a key mechanism in the development of congenital HCMV-related pathogenesis and neurodevelopmental sequelae. We explore how HCMV may perturb the complement system during pregnancy and use one inhibitor example to illustrate the broader potential of targeting complement in limiting disease. Full article

It is estimated that approximately 90% of all head and neck cancers are squamous cell carcinomas with a complex and multifactorial etiology. Molecular and epidemiological studies provide evidence for the role of oncogenic viruses in the initiation and/or oncomodulation of head and neck squamous cell carcinoma. Objectives: The present study aimed to detect the presence of high- and low-risk HPV, BKPyV, EBV, HCMV, HSVs in biopsy samples of squamous cell carcinoma of the external auricle in patients in Bulgaria. Materials and Methods: The study included 41 biopsy specimens from etiologically undiagnosed cases of squamous cell carcinoma of the external auricle. Molecular biological methods were used to detect the viruses—conventional and nested PCR, and sequence analysis. Results: The results obtained showed that none of the samples were found to have a high-risk HPV genotype. The highest percentage of samples showed genotype 6/11, and the lowest number of samples showed low-risk genotype 44. Of all herpesviruses, EBV was found in the largest proportion of samples, being present in the sample as a co-infection with HPV and always together with genotype 6/11. The frequency distribution, as a percentage and number of samples, of the possibilities for co-infection of EBV with each of the HPV genotypes was established. Of the remaining herpesviruses, the presence of HSV 2 was not confirmed in any of the samples. HSV 1 was present in only three of the samples, as a co-infection with genotypes 6/11, 42 and 43. When examining the samples for the presence of HCMV, only one positive sample was found, with both HPV 6/11 and 42 additionally present in the sample. Conclusions: For the first time, HPV, BKPyV, EBV, HCMV and HSVs were investigated and their possible involvement alone or as co-infection in the carcinogenesis of squamous cell carcinoma of the external auricle in patients in Bulgaria. The presence of the mentioned viruses, as well as the non-random distribution of EBV + HPV 6/11 and EBV + HPV 44, proven by us, does not necessarily make them etiological agents, but they could, through different and known mechanisms, influence the initiation and/or modulation of carcinogenesis. Full article