-
PLoS Pathogens Jun 2024Epstein-Barr virus (EBV) is a likely prerequisite for multiple sclerosis (MS) but the underlying mechanisms are unknown. We investigated antibody and T cell responses to...
BACKGROUND
Epstein-Barr virus (EBV) is a likely prerequisite for multiple sclerosis (MS) but the underlying mechanisms are unknown. We investigated antibody and T cell responses to EBV in persons with MS (pwMS), healthy EBV-seropositive controls (HC) and post-infectious mononucleosis (POST-IM) individuals up to 6 months after disease resolution. The ability of EBV-specific T cell responses to target antigens from the central nervous system (CNS) was also investigated.
METHODS
Untreated persons with relapsing-remitting MS, POST-IM individuals and HC were, as far as possible, matched for gender, age and HLA-DRB1*15:01. EBV load was determined by qPCR, and IgG responses to key EBV antigens were determined by ELISA, immunofluorescence and Western blot, and tetanus toxoid antibody responses by multiplex bead array. EBV-specific T cell responses were determined ex vivo by intracellular cytokine staining (ICS) and cross-reactivity of in vitro-expanded responses probed against 9 novel Modified Vaccinia Ankara (MVA) viruses expressing candidate CNS autoantigens.
RESULTS
EBV load in peripheral blood mononuclear cells (PBMC) was unchanged in pwMS compared to HC. Serologically, while tetanus toxoid responses were unchanged between groups, IgG responses to EBNA1 and virus capsid antigen (VCA) were significantly elevated (EBNA1 p = 0.0079, VCA p = 0.0298) but, importantly, IgG responses to EBNA2 and the EBNA3 family antigens were also more frequently detected in pwMS (EBNA2 p = 0.042 and EBNA3 p = 0.005). In ex vivo assays, T cell responses to autologous EBV-transformed B cells and to EBNA1 were largely unchanged numerically, but significantly increased IL-2 production was observed in response to certain stimuli in pwMS. EBV-specific polyclonal T cell lines from both MS and HC showed high levels of autoantigen recognition by ICS, and several neuronal proteins emerged as common targets including MOG, MBP, PLP and MOBP.
DISCUSSION
Elevated serum EBV-specific antibody responses in the MS group were found to extend beyond EBNA1, suggesting a larger dysregulation of EBV-specific antibody responses than previously recognised. Differences in T cell responses to EBV were more difficult to discern, however stimulating EBV-expanded polyclonal T cell lines with 9 candidate CNS autoantigens revealed a high level of autoreactivity and indicate a far-reaching ability of the virus-induced T cell compartment to damage the CNS.
Topics: Humans; Herpesvirus 4, Human; Female; Male; Epstein-Barr Virus Infections; Adult; Antibodies, Viral; Middle Aged; Cross Reactions; Multiple Sclerosis; T-Lymphocytes; Multiple Sclerosis, Relapsing-Remitting; Antigens, Viral; Viral Load; Infectious Mononucleosis; Epstein-Barr Virus Nuclear Antigens; Immunoglobulin G
PubMed: 38843296
DOI: 10.1371/journal.ppat.1012177 -
Virology Journal Jun 2024Global human activities were significantly impacted by the emergence of the coronavirus disease 2019 (COVID-19) pandemic caused by the 2019 novel coronavirus. This study...
BACKGROUND
Global human activities were significantly impacted by the emergence of the coronavirus disease 2019 (COVID-19) pandemic caused by the 2019 novel coronavirus. This study aimed to investigate the prevalence and genotype distribution of HPV infection in Central Fujian Province during the pandemic.
METHODS
Cervical samples were collected from 21,612 outpatients and 12,664 females who underwent physical examinations and HPV screening at the People's Hospital of Fujian Province in Fuzhou from April 2020 to April 2023. HPV detection and genotyping were conducted using PCR hybridization.
RESULTS
The overall HPV infection rate was 16.1% during the COVID-19 pandemic, with the outpatient group exhibiting a greater infection rate (19.0%) than did the healthy group (12.3%). The top five high-risk HPV (HR-HPV) genotypes in both groups were HPV52, HPV53, HPV58, HPV16, and HPV51. Additionally, HPV81 and HPV43 were the two most common low-risk HPV (LR-HPV) genotypes in the patient group, while HPV81 and HPV42 were the two most common LR-HPV genotypes in the healthy group. The highest prevalence of HPV infection was observed in individuals aged ≤ 24 years (28.4%, 95% CI 25.9-30.9), followed by those aged ≥ 55 years (23.6%, 95% CI 21.6-24.7) and other age groups. The prevalence decreased from 23.0% (95% CI 22.4-23.7) in 2018-2019 to 13.8% (95% CI 12.0-15.5) in 2023.
CONCLUSION
This study provides valuable insights into the prevalence and genotypes of HPV infection in the female population of Central Fujian Province from 2020 to 2023. The findings indicate that the prevalence of HPV infection in Central Fujian Province remains relatively low compared to the national average. Furthermore, the prevalence of HPV decreased during the COVID-19 pandemic; however, as the pandemic waned, there was potential for an increase in HPV infection rates. Therefore, it is crucial to strengthen HPV screening and vaccination strategies to prevent the potential spread of HPV.
Topics: Humans; Female; Papillomavirus Infections; China; Adult; Prevalence; Genotype; COVID-19; Middle Aged; Young Adult; Papillomaviridae; SARS-CoV-2; Adolescent; Aged; Cervix Uteri; Human Papillomavirus Viruses
PubMed: 38840267
DOI: 10.1186/s12985-024-02393-z -
BMC Infectious Diseases Jun 2024In January 2020, a different cervical cancer screening program started in Germany. Women above the age of 35 are recommended to have a combined HPV and cytology swab...
Risk of cervical high-grade squamous intraepithelial neoplasia in cytologic negative and persistently high-risk human papillomavirus positive patients according to genotypes: a retrospective single center analysis.
In January 2020, a different cervical cancer screening program started in Germany. Women above the age of 35 are recommended to have a combined HPV and cytology swab every three years. Showing persistent high-risk human papillomavirus (hrHPV), cytologic negative cervical samples at baseline and after 12 months, patients are referred to colposcopy. Entailing considerable additional workload due to the required colposcopies, we analyzed the risk of high-grade cervical intraepithelial neoplasia (CIN 3) in cytologic negative and persistent hrHPV women according to their hrHPV genotypes.Methods In this single center retrospective study, patients with persistent hrHPV, cytology negative cervical samples from our certified Colposcopy Unit in 2020 and 2021 were analyzed. Patient demographics, hrHPV types, biopsy rates and histological reports were collected.Results During the study, 69 patients were enrolled. Most frequent hrHPV genotypes were: hrHPV other 72.5%; HPV 16, 20.3% and HPV 18, 7.2%. Colposcopy showed no or minor changes in 92.7% and major changes in 7.2%. CIN 3 was found in 7 patients (10.1%). Prevalence of CIN 3 by hrHPV genotypes was 27.3% for HPV16, 20.0% for HPV18 and 7.1% for HPVO. A statistically significant dependency between hrHPV and cervical intraepithelial neoplasia was demonstrated (p = 0.048).Conclusion Within this single center study of persistent hrHPV, cytologic negative samples, patients with HPV 16 were more likely to have high-grade disease compared to other hrHPV subtypes. Larger prospective randomized trials are needed to substantiate our results and obtain adjusted cervical cancer screening time intervals according to the hrHPV genotypes.
Topics: Humans; Female; Retrospective Studies; Papillomavirus Infections; Adult; Genotype; Middle Aged; Uterine Cervical Neoplasms; Uterine Cervical Dysplasia; Colposcopy; Papillomaviridae; Germany; Aged; Early Detection of Cancer; Cervix Uteri; Human Papillomavirus Viruses
PubMed: 38834951
DOI: 10.1186/s12879-024-09449-z -
Scientific Reports Jun 2024BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols... (Comparative Study)
Comparative Study
A comparative analysis of clinical outcomes between conversion to mTOR inhibitor and calcineurin inhibitor reduction in managing BK viremia among kidney transplant patients.
BK virus-associated nephropathy (BKVAN) exerts a substantial impact on allograft survival, however, the absence of robust clinical evidence regarding treatment protocols adds to the complexity of managing this condition. This study aimed to compare the two treatment approaches. The study population consisted of patients who underwent kidney transplantation between January 2016 and June 2020 at two tertiary hospitals in Korea. Patients diagnosed with BK viremia were evaluated based on their initial viral load and the treatment methods. The 'Reduction group' involved dose reduction of tacrolimus while the 'Conversion group' included tacrolimus discontinuation and conversion to sirolimus. A total of 175 patients with an initial viral load (iVL) ≥ 3 on the log10 scale were evaluated within two iVL intervals (3-4 and 4-5). In the iVL 4-5 interval, the Reduction group showed potential effectiveness in terms of viral clearance without statistically significant differences. However, within the iVL 3-4 interval, the Reduction group demonstrated superior viral clearance and a lower incidence of biopsy-proven acute rejection (BPAR) than the Conversion group. The renal function over 12 months after BKV diagnosis showed no statistically significant difference. Reducing tacrolimus compared to converting to mTORi would be a more appropriate treatment approach for BK viral clearance in kidney transplantation. Further research is warranted in a large cohort of patients.
Topics: Humans; Kidney Transplantation; Male; Female; BK Virus; Middle Aged; Calcineurin Inhibitors; Viremia; Polyomavirus Infections; Tacrolimus; Adult; TOR Serine-Threonine Kinases; Immunosuppressive Agents; Viral Load; Treatment Outcome; Tumor Virus Infections; Graft Rejection; Sirolimus; Republic of Korea; Retrospective Studies; Aged
PubMed: 38834615
DOI: 10.1038/s41598-024-60695-2 -
Virology Journal Jun 2024Merkel Cell Carcinoma (MCC) is an aggressive skin cancer that is three times deadlier than melanoma. In 2008, it was found that 80% of MCC cases are caused by the...
The small tumor antigen of Merkel cell polyomavirus accomplishes cellular transformation by uniquely localizing to the nucleus despite the absence of a known nuclear localization signal.
BACKGROUND
Merkel Cell Carcinoma (MCC) is an aggressive skin cancer that is three times deadlier than melanoma. In 2008, it was found that 80% of MCC cases are caused by the genomic integration of a novel polyomavirus, Merkel Cell Polyomavirus (MCPyV), and the expression of its small and truncated large tumor antigens (ST and LT-t, respectively). MCPyV belongs to a family of human polyomaviruses; however, it is the only one with a clear association to cancer.
METHODS
To investigate the role and mechanisms of various polyomavirus tumor antigens in cellular transformation, Rat-2 and 293A cells were transduced with pLENTI MCPyV LT-t, MCPyV ST, TSPyV ST, HPyV7 ST, or empty pLENTI and assessed through multiple transformation assays, and subcellular fractionations. One-way ANOVA tests were used to assess statistical significance.
RESULTS
Soft agar, proliferation, doubling time, glucose uptake, and serum dependence assays confirmed ST to be the dominant transforming protein of MCPyV. Furthermore, it was found that MCPyV ST is uniquely transforming, as the ST antigens of other non-oncogenic human polyomaviruses such as Trichodysplasia Spinulosa-Associated Polyomavirus (TSPyV) and Human Polyomavirus 7 (HPyV7) were not transforming when similarly assessed. Identification of structural dissimilarities between transforming and non-transforming tumor antigens revealed that the uniquely transforming domain(s) of MCPyV ST are likely located within the structurally dissimilar loops of the MCPyV ST unique region. Of all known MCPyV ST cellular interactors, 62% are exclusively or transiently nuclear, suggesting that MCPyV ST localizes to the nucleus despite the absence of a canonical nuclear localization signal. Indeed, subcellular fractionations confirmed that MCPyV ST could achieve nuclear localization through a currently unknown, regulated mechanism independent of its small size, as HPyV7 and TSPyV ST proteins were incapable of nuclear translocation. Although nuclear localization was found to be important for several transforming properties of MCPyV ST, some properties were also performed by a cytoplasmic sequestered MCPyV ST, suggesting that MCPyV ST may perform different transforming functions in individual subcellular compartments.
CONCLUSIONS
Together, these data further elucidate the unique differences between MCPyV ST and other polyomavirus ST proteins necessary to understand MCPyV as the only known human oncogenic polyomavirus.
Topics: Merkel cell polyomavirus; Humans; Antigens, Viral, Tumor; Cell Nucleus; Animals; Rats; Nuclear Localization Signals; Carcinoma, Merkel Cell; Cell Line; Skin Neoplasms; Cell Transformation, Viral; Antigens, Polyomavirus Transforming; Polyomavirus Infections
PubMed: 38831469
DOI: 10.1186/s12985-024-02395-x -
BMC Public Health Jun 2024The prevalence of, and risk factors for, genital Human Papillomavirus (HPV) infections within the young adult population are well-established; the same is not known for... (Observational Study)
Observational Study
BACKGROUND
The prevalence of, and risk factors for, genital Human Papillomavirus (HPV) infections within the young adult population are well-established; the same is not known for oral HPV. This observational study aimed to determine oral HPV prevalence and abundance within a UK young adult population, and examine if sexual practices and established risk factors of oropharyngeal squamous cell carcinomas (OPSCCs) (such as smoking and alcohol consumption) influenced HPV prevalence.
METHODS
Convenience sampling was used to recruit a small sample of 452 UK-based young adults studying at a higher education (HE) institution to the study; the study was not powered. A highly sensitive real-time PCR HPV screening method was developed for the detection of multiple HPV subtypes from oral swabs. HPV-positive samples were subsequently screened by qPCR for viral subtypes HPV-6, HPV-11, HPV-16, HPV-18. Results were analysed by univariate and multivariate methods and stratified for gender, with lifestyle behaviour data collected via questionnaire. Socio-economic status was not captured within the questionnaire.
RESULTS
We found a high oral HPV prevalence of 22.79%, with a dominance of high-risk viral type HPV-16 (prevalence 19.12%; abundance average 1.08 × 10 copies/million cells) detected within healthy young adults. Frequent smoking (p = .05), masturbation (p = .029), and engagement in multiple sexual activities (p = .057), were found to be associated with oral HPV prevalence, and HPV-16 prevalence, whilst behaviours traditionally associated with genital HPV were not.
CONCLUSIONS
Our results strengthen the link between sexual practices and oral HPV transmission. We suggest that young adults should be considered high-risk for the contraction of oral HPV, although acknowledge that this sample of HE students may not be representative of the wider population. We show that high-risk HPV-16 is prevalent in the healthy population, as well as dominating within OPSCC; this study is one of the first to determine the dominance of oral HPV-16 prevalence and abundance within this population, presenting a clear need for greater awareness of oral HPV infections, and the risk factors for HPV-positive OPSCC within young adults.
Topics: Humans; Papillomavirus Infections; Male; Female; Risk Factors; Prevalence; Young Adult; United Kingdom; Sexual Behavior; Adult; Adolescent; Oropharyngeal Neoplasms; Papillomaviridae; Real-Time Polymerase Chain Reaction; Human Papillomavirus Viruses
PubMed: 38831431
DOI: 10.1186/s12889-024-18977-x -
BMC Infectious Diseases Jun 2024Persistent infections with high-risk human papillomavirus (hrHPV) can cause cervical squamous intraepithelial lesions (SIL) that may progress to cancer. The...
BACKGROUND
Persistent infections with high-risk human papillomavirus (hrHPV) can cause cervical squamous intraepithelial lesions (SIL) that may progress to cancer. The cervicovaginal microbiome (CVM) correlates with SIL, but the temporal composition of the CVM after hrHPV infections has not been fully clarified.
METHODS
To determine the association between the CVM composition and infection outcome, we applied high-resolution microbiome profiling using the circular probe-based RNA sequencing technology on a longitudinal cohort of cervical smears obtained from 141 hrHPV DNA-positive women with normal cytology at first visit, of whom 51 were diagnosed by cytology with SIL six months later.
RESULTS
Here we show that women with a microbial community characterized by low diversity and high Lactobacillus crispatus abundance at both visits exhibit low risk to SIL development, while women with a microbial community characterized by high diversity and Lactobacillus depletion at first visit have a higher risk of developing SIL. At the level of individual species, we observed that a high abundance for Gardnerella vaginalis and Atopobium vaginae at both visits associate with SIL outcomes. These species together with Dialister micraerophilus showed a moderate discriminatory power for hrHPV infection progression.
CONCLUSIONS
Our results suggest that the CVM can potentially be used as a biomarker for cervical disease and SIL development after hrHPV infection diagnosis with implications on cervical cancer prevention strategies and treatment of SIL.
Topics: Humans; Female; Longitudinal Studies; Vagina; Microbiota; Papillomavirus Infections; Adult; Cervix Uteri; Middle Aged; Papillomaviridae; Young Adult; Uterine Cervical Neoplasms; Vaginal Smears
PubMed: 38831406
DOI: 10.1186/s12879-024-09455-1 -
CMAJ : Canadian Medical Association... Jun 2024
Topics: Humans; Canada; Female; Uterine Cervical Neoplasms; Papillomavirus Infections; Specimen Handling; Vaginal Smears; Self Care; Early Detection of Cancer; Papillomaviridae; Human Papillomavirus Viruses
PubMed: 38830678
DOI: 10.1503/cmaj.240722 -
Microbiology Spectrum Jul 2024The incidence rate of human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is increasing in countries with high human development index. HPV cell-free DNA (cfDNA)...
The incidence rate of human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is increasing in countries with high human development index. HPV cell-free DNA (cfDNA) isolated from 3 to 4 mL blood plasma has been successfully used for therapy surveillance. A highly discussed application of HPV-cfDNA is early detection of HPV-OPC. This requires sensitive and specific cfDNA detection as cfDNA levels can be very low. To study the predictive power of pre-diagnostic HPV-cfDNA, archived samples from epidemiological cohorts with limited plasma volume are an important source. To establish a cfDNA detection workflow for low plasma volumes, we compared cfDNA purification methods [MagNA Pure 96 (MP96) and QIAamp ccfDNA/RNA] and digital PCR systems (Biorad QX200 and QIAGEN QIAcuity One). Final assay validation included 65 low-volume plasma samples from oropharyngeal cancer (OPC) patients with defined HPV status stored for 2-9 years. MP96 yielded a 28% higher cfDNA isolation efficiency in comparison to QIAamp. Both digital PCR systems showed comparable analytical sensitivity (6-17 copies for HPV16 and HPV33), but QIAcuity detected both types in the same assay. In the validation set, the assay had 80% sensitivity ( = 28/35) for HPV16 and HPV33 and a specificity of 97% ( = 29/30). In samples with ≥750 µL plasma, the sensitivity was 85% ( = 17/20), while in samples with <750 µL plasma, it was 73% ( = 11/15). Despite the expected drop in sensitivity with decreased plasma volume, the assay is sensitive and highly specific even in low-volume samples and thus suited for studies exploring HPV-cfDNA as an early HPV-OPC detection marker in low-volume archival material.IMPORTANCEHPV-OPC has a favorable prognosis compared to HPV-negative OPC. However, the majority of tumors is diagnosed after regional spread, thus making intensive treatment necessary. This can cause lasting morbidity with a large impact on quality of life. One potential method to decrease treatment-related morbidity is early detection of the cancer. HPV cfDNA has been successfully used for therapy surveillance and has also been detected in pre-diagnostic samples of HPV-OPC patients. These pre-diagnostic samples are only commonly available from biobanks, which usually only have small volumes of blood plasma available. Hence, we have developed a workflow optimized for small-volume archival samples. With this method, a high sensitivity can be achieved despite sample limitations, making it suitable to conduct further large-scale biobank studies of HPV-cfDNA as a prognostic biomarker for HPV-OPC.
Topics: Humans; DNA, Viral; Papillomavirus Infections; Cell-Free Nucleic Acids; Polymerase Chain Reaction; Oropharyngeal Neoplasms; Papillomaviridae; Female; Sensitivity and Specificity; Male; Middle Aged; Aged; Human papillomavirus 16; Human Papillomavirus Viruses
PubMed: 38829114
DOI: 10.1128/spectrum.00024-24 -
Cancer Medicine Jun 2024To assess the clinical values of extended human papillomavirus (HPV) genotyping in triage of high-risk HPV-positive women, focusing on the trade-off between cervical...
Clinical evaluation of primary human papillomavirus (HPV) testing with extended HPV genotyping triage for cervical cancer screening: A pooled analysis of individual patient data from nine population-based cervical cancer screening studies from China.
OBJECTIVE
To assess the clinical values of extended human papillomavirus (HPV) genotyping in triage of high-risk HPV-positive women, focusing on the trade-off between cervical precancer detections and colposcopy referrals.
METHODS
A bivariate random-effects model was used to estimate the diagnostic accuracy of primary HPV screening with following triage strategies to detect cervical precancers: (i) partial genotyping for HPV16/18 combined with cytological testing at atypical squamous cells of undetermined significance threshold (used as the comparator), (ii) genotyping for HPV16/18/58/52, (iii) genotyping for HPV16/18/58/52/33, (iv) genotyping for HPV16/18/58/33/31, (v) genotyping for HPV16/18/58/52/33/31, and (vi) genotyping for HPV16/18/58/52/33/31/39/51. Internal risk benchmarks for clinical management were used to evaluate the risk stratification of each triage strategy.
RESULTS
A total of 16,982 women (mean age 46.1 years, range 17-69) were included in this analysis. For CIN3+ detection, triage with HPV16/18/58/33/31 genotyping achieved lower positivity (6.85% vs. 7.35%, p = 0.001), while maintaining similar sensitivity (91.35% vs. 96.42%, p = 0.32) and specificity (94.09% vs. 93.67%, p = 0.56) compared with the comparator strategy. Similar patterns were observed for CIN2+ detection. Women with a positive HPV16/18/58/33/31 genotyping test had high enough risk for CIN3+ for colposcopy referral, while the risk for women with a negative test was below the 1-year return decision threshold according to internal benchmarks.
CONCLUSIONS
Our findings suggested extended HPV genotyping is of potential to be used as a triage technique integrated into HPV-based cervical cancer screening, leading to reduced need for colposcopy referral while maintaining similar disease detection and efficient risk stratification.
Topics: Humans; Female; Uterine Cervical Neoplasms; Early Detection of Cancer; Adult; Papillomavirus Infections; Middle Aged; Triage; China; Adolescent; Young Adult; Genotype; Colposcopy; Papillomaviridae; Uterine Cervical Dysplasia; Aged; Human papillomavirus 18; Sensitivity and Specificity; Human Papillomavirus Viruses
PubMed: 38828559
DOI: 10.1002/cam4.7316