Review on the role of the human Polyomavirus JC in the development of tumors

Almost one fifth of human cancers worldwide are associated with infectious agents, either bacteria or viruses, and this makes the possible association between infections and tumors a relevant research issue. We focused our attention on the human Polyomavirus JC (JCPyV), that is a small, naked DNA virus, belonging to the Polyomaviridae family. It is the recognized etiological agent of the Progressive Multifocal Leukoencephalopathy (PML), a fatal demyelinating disease, occurring in immunosuppressed individuals. JCPyV is able to induce cell transformation in vitro when infecting non-permissive cells, that do not support viral replication and JCPyV inoculation into small animal models and non human primates drives to tumor formation. The molecular mechanisms involved in JCPyV oncogenesis have been extensively studied: the main oncogenic viral protein is the large tumor antigen (T-Ag), that is able to bind, among other cellular factors, both Retinoblastoma protein (pRb) and p53 and to dysregulate the cell cycle, but also the early proteins small tumor antigen (t-Ag) and Agnoprotein appear to cooperate in the process of cell transformation. Consequently, it is not surprising that JCPyV genomic sequences and protein expression have been detected in Central Nervous System (CNS) tumors and colon cancer and an association between this virus and several brain and non CNS-tumors has been proposed. However, the significances of these findings are under debate because there is still insufficient evidence of a casual association between JCPyV and solid cancer development. In this paper we summarized and critically analyzed the published literature, in order to describe the current knowledge on the possible role of JCPyV in the development of human tumor

Chapter Longitudinal profile of a set of biomarkers in predicting Covid-19 mortality using joint models

In survival analysis, time-varying covariates are endogenous when their measurements are directly related to the event status and incomplete information occur at random points during the follow-up. Consequently, the time-dependent Cox model leads to biased estimates. Joint models (JM) allow to correctly estimate these associations combining a survival and longitudinal sub-models by means of a shared parameter (i.e., random effects of the longitudinal sub-model are inserted in the survival one). This study aims at showing the use of JM to evaluate the association between a set of inflammatory biomarkers and Covid-19 mortality. During Covid-19 pandemic, physicians at Istituto Clinico di Città Studi in Milan collected biomarkers (endogenous time-varying covariates) to understand what might be used as prognostic factors for mortality. Furthermore, in the first epidemic outbreak, physicians did not have standard clinical protocols for management of Covid-19 disease and measurements of biomarkers were highly incomplete especially at the baseline. Between February and March 2020, a total of 403 COVID-19 patients were admitted. Baseline characteristics included sex and age, whereas biomarkers measurements, during hospital stay, included log-ferritin, log-lymphocytes, log-neutrophil granulocytes, log-C-reactive protein, glucose and LDH. A Bayesian approach using Markov chain Monte Carlo algorithm were used for fitting JM. Independent and non-informative priors for the fixed effects (age and sex) and for shared parameters were used. Hazard ratios (HR) from a (biased) time-dependent Cox and joint models for log-ferritin levels were 2.10 (1.67-2.64) and 1.73 (1.38-2.20), respectively. In multivariable JM, doubling of biomarker levels resulted in a significantly increase of mortality risk for log-neutrophil granulocytes, HR=1.78 (1.16-2.69); for log-C-reactive protein, HR=1.44 (1.13-1.83); and for LDH, HR=1.28 (1.09-1.49). Increasing of 100 mg/dl of glucose resulted in a HR=2.44 (1.28-4.26). Age, however, showed the strongest effect with mortality risk starting to rise from 60 years

Novel antiviral activity of PAD inhibitors against human beta-coronaviruses HCoV-OC43 and SARS-CoV-2

The current SARS-CoV-2 pandemic, along with the likelihood that new coronavirus strains will appear in the nearby future, highlights the urgent need to develop new effective antiviral agents. In this scenario, emerging host-targeting antivirals (HTAs), which act on host-cell factors essential for viral replication, are a promising class of antiviral compounds. Here we show that a new class of HTAs targeting peptidylarginine deiminases (PADs), a family of calcium-dependent enzymes catalyzing protein citrullination, is endowed with a potent inhibitory activity against human beta-coronaviruses (HCoVs). Specifically, we show that infection of human fetal lung fibroblasts with HCoV-OC43 leads to enhanced protein citrullination through transcriptional activation of PAD4, and that inhibition of PAD4-mediated citrullination with either of the two pan-PAD inhibitors Cl-A and BB-Cl or the PAD4-specific inhibitor GSK199 curbs HCoV-OC43 replication. Furthermore, we show that either Cl-A or BB-Cl treatment of African green monkey kidney Vero-E6 cells, a widely used cell system to study beta-CoV replication, potently suppresses HCoV-OC43 and SARS-CoV-2 replication. Overall, our results demonstrate the potential efficacy of PAD inhibitors, in suppressing HCoV infection, which may provide the rationale for the repurposing of this class of inhibitors for the treatment of COVID-19 patients

Characterization of an in vitro model to study the role of human Polyomavirus BK in prostate cancer

Prostate cancer (PCa) is one of the most common male neoplasm in the western world, being the most commonly diagnosed non-skin cancer and the second leading cause of cancer death. Various potential risk factors exist for the initial triggering events, including exposure to infectious agents, such as the human Polyomavirus BK (BKV). BKV is a good candidate as risk factor of PCa because it naturally infects the human reno-urinary tract, it establishes latency, and encodes oncoproteins that interfere with tumor suppressors pathways, thus altering the normal progression of cell cycle. Previous studies suggested a potential association between BKV and PCa, revealing that the prevalence of BKV was significantly higher in cancer than in control tissues, with a significant association between viral expression and cancer. However, this hypothesis is controversial because BKV is not restricted to tumor tissues but also infects healthy individuals in a high percentage. Moreover, an in vitro model of BKV infection in prostate cells is not available to understand the role for BKV in pathogenesis of PCa. Our aims were to determine whether BKV a) could infect normal epithelial prostate cells, b) affects cell phenotype and c) affects the phenotype of human prostate tumor cell line PC3. For this purpose normal epithelial prostate cell line RWPE-1 and prostate cancer cells PC3 were infected with BKV for 21 days. Cell proliferation, epithelial-to-mesenchymal markers (EMT) and invasion potential were analyzed by, respectively, MTT, immunofluorescence and SDS-zymography. Our results show that cell proliferation was increased or decreased by BKV, respectively, in RWPE-1 and PC3 cells. BKV induced E-cadherin downregulation and vimentin expression in both control and BKV-infected cells RWPE-1, suggesting that uninfected cells underwent EMT. Matrix metalloproteinase-2 and 9 activity was increased in RWPE-1 cells after BKV infection. By contrast, BKV did not significantly modified the phenotype of PC3 cells. These preliminary results suggest that normal epithelial prostate cells RWPE-1 and PC3 are susceptible and permissive to BKV infection. However, RWPE-1 cells exhibit some phenotype modifications related to EMT, possibly induced by the papilloma virus used to obtain their immortalization, thus suggesting that further experiments will be necessary to define if they represent a good experimental model to study prostate cancer

Molecular epidemiology of non-viral sexually transmitted infections in the central Alpine province of Bolzano, northern Italy from April 2016 to March 2017

Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis and Mycoplasma genitalium are established or presumed as (??) STI pathogens. The present study aims at ng describing the one-year molecular epidemiology of these seven pathogens in the Province of Bolzano, Northern Italy. From April 2016 to March 2017, a total of 2,949 patients, mainly females, were enrolled and 3,427 urine, vaginal, endocervical and/or urethral samples were subjected to simultaneous analysis of the seven pathogens by means of Real Time Polymerase Chain Reaction (AnyplexTM II STI-7 Detection Kit Seegene, Seoul, Korea). At least one of the seven microorganisms was detected in 40.7% of patients, with an uneven distribution: 43.1% in females (F) and 29.8% (p<0.001) in males (M). The prevalence of microorganisms was as follows: 30.3% U. parvum (F: 35.6%, M: 8.3%), 6.9% U. urealyticum (F: 6.8%, M: 7.0%), 4.9% M. hominis (F: 5.4%, M: 2.3%), 4.9% C. trachomatis (F: 3.4%, M: 11.4%), 1.1% M. genitalium (F: 1.0%, M: 1.2%), 1.2% N. gonorrhoeae (F: 0.17%, M: 5.6%) and 0.40% T. vaginalis (F: 0.38%, M: 0.53%). Mixed infections were detected in 7.4% of patients. The highest prevalence was observed for U. parvum, followed by U. urealyticum and M. hominis and a significant presence of multi-pathogen infections was registered

BK virus associated meningoencephalitis in an AIDS patient treated with HAART

A severely immune-suppressed AIDS patient was suspected of suffering from BK virus (BKV) meningoencephalitis, after being studied for common causes of neurological complications of co-infectious origin. Polymerase chain reaction (PCR) and sequence analysis of cerebrospinal fluid and brain samples, confirmed the presence of BKV. His clinical condition improved along with the regression of brain lesions, after modifications on his antiretroviral regime. Five months after discharge, the patient was readmitted because of frequent headaches, and a marked inflammatory reaction was evidenced by a new magnetic resonance imaging (MRI). The symptoms paralleled a rising CD4+ lymphocyte count, and immune reconstitution syndrome was suspected. This is the first non-postmortem report of BKV meningoencephalitis in an AIDS patient, showing clinical and radiographic improvement solely under HAART

Nirmatrelvir treatment of SARS-CoV-2-infected mice blunts antiviral adaptive immune responses

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir-an orally available inhibitor of the 3-chymotrypsin-like cysteine protease-has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using mouse models of SARS-CoV-2 infection, we show that nirmatrelvir administration blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals

Polyomavirus BK and prostate cancer: an unworthy scientific effort?

The Polyomavirus BK (BKV) has been proposed to be one of the possible co-factors in the genesis of prostate cancer (PCa) but, so far, the only convincing suggestion is the hypothesis of a “hit and run” carcinogenic mechanism induced by the virus at early stages of this disease. To support this hypothesis we conducted an updated systematic review on previous studies regarding the association between BKV and PCa, in order to interpret the contrasting results and to explore whether there might be a significant virus-disease link. This updated analysis provides evidence for a significant link between BKV expression and PCa development, particularly between the BKV infection and the cancer risk. Forthcoming scientific efforts that take cue from this study might overcome the atavistic and fruitless debate regarding the BKV-PCa association

Review on the Relationship between Human Polyomaviruses-Associated Tumors and Host Immune System

The polyomaviruses are small DNA viruses that can establish latency in the human host. The name polyomavirus is derived from the Greek roots poly-, which means “many,” and -oma, which means “tumours.” These viruses were originally isolated in mouse (mPyV) and in monkey (SV40). In 1971, the first human polyomaviruses BK and JC were isolated and subsequently demonstrated to be ubiquitous in the human population. To date, at least nine members of the Polyomaviridae family have been identified, some of them playing an etiological role in malignancies in immunosuppressed patients. Here, we describe the biology of human polyomaviruses, their nonmalignant and malignant potentials ability, and their relationship with the host immune response

Polyomavirus BK and prostate cancer: a complex interaction of potential clinical relevance

Several studies associating BK polyomavirus (BKPyV) and prostate cancer (PCa) suggested that this virus may exert its oncogenic activity at early stages of cancer development. The BKPyV oncogene, the large T antigen (LTag), has frequently been detected in areas of proliferative inflammatory atrophy, which is considered a precursor lesion leading to prostatic intraepithelial neoplasia and overt PCa. In a recently updated systematic review, the presence of BKPyV was significantly higher in PCa tissues than in healthy control tissues, providing an indication for a link between BKPyV infection and cancer risk. In addition, recent original investigations highlighted an association between expression of the virus and the clinical course of PCa. For example, by studying immune responses elicited against BKPyV LTag, a significant association between LTag positive cancer lesions and a peculiar regulatory profiling has been observed in PCa patients with evidence of disease recurrence after surgical radical prostatectomy. Lastly, a study carried out in a larger cohort of patients undergoing radical prostatectomy revealed the IgG response against LTag as an independent predictor of disease recurrence. Although a full picture of the mechanisms potentially responsible for the involvement of BKPyV in PCa is not available yet, continuing work on this topic should help to refine the potential role of BKPyV in PCa patients, perhaps revealing unsuspected associations with the clinical course of this disease. Copyright © 2015 John Wiley & Sons, Ltd