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PubMed2025

A randomized pilot study of HPV16 L2E7E6 fusion protein vaccination site post-treatment for HPV16+ cervical cancer.

OBJECTIVE: Since anti-tumor immunity is enhanced by vaccination of mice adjacent to human papillomavirus type 16 (HPV16+) tumors, we examined whether HPV16 L2E7E6 fusion protein (TA-CIN) vaccination in the thigh of HPV16+ cervical cancer patients would be more immunogenic than their arm. METHODS: HPV16+ cervical cancer (stage IB1-IVA) patients, who had completed standard-of-care treatment within the past year and absent evidence of disease (NED), were enrolled in a pilot study (NCT02405221). Participants were randomized 1:1 to receive three 100 μg TA-CIN monthly intramuscular immunizations either in the arm or thigh and followed for two years for safety (CTCAEv4.0), immune response, and recurrence. RESULTS: Fifteen patients were enrolled (median age 44, range 35-83 years); one patient experienced a non-vaccine-related adverse event after one vaccination and withdrew. Treatment-related adverse events (n = 8) were grade 1, primarily at the injection site, and self-resolved. No recurrence was observed. TA-CIN-specific antibody titers tended to be higher in thigh-vaccinated patients. Bulk TCRseq revealed significant increases in expanded and de novo T cell clones following thigh-vaccination compared with the arm. No correlation with prior treatment modality was observed. E6-, E7-, and L2-specific TCR clones expanded, although L2-specific T cell responses were predominant. One month post-vaccination, scRNAseq revealed significant expansion of MAIT and cytotoxic CD8+ T cells, and both expanded and novel TCR clonotypes were identified in the latter. CONCLUSIONS: Thigh or arm vaccination with TA-CIN was well tolerated, but the former elicited higher CD8 T cell and antibody responses in HPV16+ cervical cancer patients with NED after primary therapy.

Humans↗

PubMed2026

Association of HPV16 infection with p53 and survivin expression in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity and a major public health concern worldwide. This study aimed to investigate the relationship between p53 and survivin expression, clinicopathologic parameters and HPV16 infection in OSCC in order to elucidate the potential role of HPV16 in its pathogenesis.The study enrolled 45 patients who underwent surgical treatment for histologically confirmed OSCC. Tumor specimens were formalin-fixed and paraffin-embedded (FFPE) and histologically analyzed using hematoxylin/eosin staining. Immunohistochemistry for p53 and survivin was performed using the DAKO system. DNA extracted from FFPE tumor tissues was analyzed for HPV16 genome presence using polymerase chain reaction (PCR). All patients were followed for three years after primary treatment.No statistically significant associations were observed between p53 or survivin expression and clinicopathologic parameters including age, gender, tumor site, grade, stage, recurrence, metastasis or HPV16 status (P > 0.05). Among HPV16-positive patients (11/45, 24.4%), low survivin expression (<5%) was found in 8/11 (73%) patients, while high p53 expression (>10%) was observed in 7/11 (64%) patients. Disease-free interval did not differ significantly between patients with low vs. high p53 (P = 0.220) or survivin expression (P = 0.580). A significant correlation was detected between p53 and survivin expression (P = 0.04). HPV16 positivity was significantly associated with the absence of p53 immunoreactivity.These findings suggest that HPV16-independent oncogenic pathways are likely predominant in OSCC, while HPV16 infection may be associated with a distinct molecular subset characterized by absent p53 expression (p53-; survivin+/-; HPV16+). These results underscore the biological heterogeneity of OSCC and may have implications for future biomarker-based stratification of patients.

HPV16↗

PubMed2026

Regulation and function of the HPV16 CircE7 RNA.

High-risk human papillomaviruses (HPV), including HPV16, produce circular RNA that encompasses the E7 oncogene (circE7). CircE7 can be detected in HPV16-positive cells and tumors, is preferentially localized to the cytoplasm, is N6-methyladenosine (m6A)-modified, and can be translated into the E7 oncoprotein. Here, we explored the regulation and function of circE7. Mutation of m6A motifs flanking the backsplice junction revealed a single m6A motif to be essential for circE7 formation. Mutation of this m6A motif promoted linear splicing of the E6*I splice site (226^409), suggesting that linear and circular E7 splicing are inversely regulated. Additionally, mutation of an IRES-like motif in circE7 significantly decreased E7 protein expression, without having significant effects on circE7 RNA levels. Knockdown of YTHDC1, but not other m6A-binding proteins, decreased both circE7 RNA and protein expression. BaseScope ISH was used to confirm the expression of circE7 in head and neck squamous cell carcinoma cell lines and tumors. Using both qRT-PCR and BaseScope ISH, we found that serum and amino acid starvation significantly increased circE7. Finally, we generated an HPV16 genome with mutations in the circE7 m6A motif (Mut2). Stable transduction of primary keratinocytes with Mut2 confirmed the loss of circE7 and increased expression of E6*I. The Mut2 HPV16 genome exhibited significantly decreased viral replication but an increased ability to transform primary keratinocytes. Our studies reveal that the precise regulation of circE7 and E6*I by m6A is critical for the ability of HPV16 to infect and transform keratinocytes.IMPORTANCEHigh-risk human papillomaviruses (HPVs), such as HPV16, must carefully control how much E6 and E7 proteins they make. This study shows that HPV16 toggles a single chemical tag on the viral RNA (an m⁶A mark) to control the production of early region RNAs, including a circular RNA called circE7. The same site coordinately regulates splicing of the E6*I isoform. CircE7 uses m⁶A-binding proteins to control its production and a specific sequence to promote its translation. It is present in HPV-positive cancers and can respond to nutrient starvation. Regulation of circE7 through this m6A site also impacted viral replication and transformation capacity, indicating that this regulatory mechanism is critical for HPV biology.

RNA splicing↗

PubMed2025

Genome-Wide Association Analyses of HPV16 and HPV18 Seropositivity Identify Susceptibility Loci for Cervical Cancer.

Infection by high-risk human papillomavirus is known to exacerbate cervical cancer development. The host immune response is crucial in disease regression. Large-scale genetic association studies for cervical cancer have identified few susceptibility variants, mainly at the human leukocyte antigen locus on chromosome 6. We hypothesized that the host immune response modifies cervical cancer risk and performed three genome-wide association analyses for HPV16, HPV18 and HPV16/18 seropositivity in 7814, 7924, and 7924 samples from the UK Biobank, followed by validation genotyping in the German Cervigen case-control series of cervical cancer and dysplasia. In GWAS analyses, we identified two loci associated with HPV16 seropositivity (6p21.32 and 15q26.2), two loci associated with HPV18 seropositivity (5q31.2 and 14q24.3), and one locus for HPV16 and/or HPV18 seropositivity (at 6p21.32). MAGMA gene-based analysis identified HLA-DQA1 and HLA-DQB1 as genome-wide significant (GWS) genes. In validation genotyping, the genome-wide significant lead variant at 6p21.32, rs9272293 associated with overall cervical disease (OR = 0.86, p = 0.004, 95% CI = 0.78-0.95, n = 3710) and HPV16 positive invasive cancer (OR = 0.73, p = 0.005, 95% CI = 0.59-0.91, n = 1431). This variant was found to be a robust eQTL for HLA-DRB1, HLA-DQB1-AS1, C4B, HLA-DRB5, HLA-DRB6, HLA-DQB1, and HLA-DPB1 in a series of cervical epithelial tissue samples. We additionally genotyped twenty-four HPV seropositivity variants below the GWS threshold out of which eleven variants were found to be associated with cervical disease in our cohort, suggesting that further seropositivity variants may determine cervical disease outcome. Our study identifies novel genomic risk loci that associate with HPV type-specific cervical cancer and dysplasia risk and provides evidence for candidate genes at one of the risk loci.

Humans↗

PubMed2025

Higher Expression of HPV16 Derived E7_LI Transcript Observed in Men With HIV and Recurrent Anal Cancer.

Squamous cell carcinoma of the anus (SCCA) or anal cancer (AC) is an understudied cancer with a high occurrence rate in people with HIV (PWH), especially men having sex with men (MSM). Furthermore, AC recurs in approximately one-fourth of patients who undergo standard care with chemoradiation therapy (CRT). Using bulk RNA sequencing data of AC obtained from 12 patients with non-recurrent (NR, N = 9) or recurrent (R, N = 3) cancer, we previously showed upregulated expression of key immune genes in the NR compared to the R group. Although the main causative agent of AC is high-risk human papillomavirus (HPV), association of host and viral RNA transcript expression contributing to AC recurrence has not been extensively studied. The objective of the current study was to determine whether enrichment of specific HPV genotypes and/or HPV gene expression patterns differentiate the two groups and if any specific viral (HPV) and host (human) immune mediators correlate with each other. Using bulk RNA sequencing data and VIRTUS 2, we detected viral RNA reads mapping to seven high-risk and six low-risk HPV types, of which the high-risk HPV16 observed in 83% (10/12) AC tumors (7/9 NR and 3/3 R). Rate of all HPV genomes trended toward a decrease in NR AC isolates and correlation between HPV types was more commonly observed in low-risk ones. Analysis of HPV 16 gene expression profile showed a significantly lower positivity rate for a polycistronic transcript encoding for E7^L1 in the NR group (1/9, NR vs. 3/3, R, p < 0.05). An unbiased correlation analysis of HPV-human transcript expression showed a direct correlation between HPV transcripts and human genes involved in cell growth. The data also identified human transcripts showing an inverse correlation with HPV gene expression. These included genes involved in negative regulation of growth, proliferation, and immune response. Taken together, these data indicate that concurrent analyses of viral and host factors in the same tumor can identify potential new therapeutic targets to ameliorate cancer recurrence post-treatment.

Humans↗

PubMed2024

Analysis of human papillomavirus type 16 E4, E5 and L2 gene variations among women with cervical infection in Xinjiang, China.

BACKGROUND: There is a high incidence of cervical cancer in Xinjiang. Genetic variation in human papillomavirus may increase its ability to invade, spread, and escape host immune response. METHODS: HPV16 genome was sequenced for 90 positive samples of HPV16 infection. Sequences of the E4, E5 and L2 genes were analysed to reveal sequence variation of HPV16 in Xinjiang and the distribution of variation among the positive samples of HPV16 infection. RESULTS: Eighty-one of the 90 samples of HPV16 infection showed variation in HPV16 E4 gene with 18 nucleotide variation sites, of which 8 sites were synonymous variations and 11 missense variations. 90 samples of HPV16 infection showed variation in HPV16 E5 and L2 genes with 16 nucleotide variation sites (6 synonymous, 11 missense variations) in the E5 gene and 100 nucleotide variation sites in L2 gene (37 synonymous, 67 missense variations). The frequency of HPV16 L2 gene missense variations G3377A, G3599A, G3703A, and G3757A was higher in the case groups than in the control groups. CONCLUSIONS: Phylogenetic tree analysis showed that 87 samples were European strains, 3 cases were Asian strains, there were no other variations, and G4181A was related to Asian strains. HPV16 L2 gene missense variations G3377A, G3599A, G3703A, and G3757A were significantly more frequent in the case groups than in the control groups.

Humans↗

PubMed2026

Immunogenicity and safety of prophylactic HPV vaccines in people living with HIV: A systematic review and meta-analysis.

Human papillomavirus (HPV) is a major global public health concern, causing genital warts and cancers of the cervix, anus, oropharynx, vulva, and penis. People living with HIV (PLWH) face a disproportionately elevated burden of HPV infection and HPV-related malignancies due to chronic immunosuppression. We conducted a systematic review and meta-analysis searching six databases from January 2006 to June 2026 without language restrictions. Twenty-five studies were included in the systematic review; 12 independent studies (N = 1,493 for HPV16) were included in the quantitative meta-analysis. Using a DerSimonian-Laird random-effects model with logit transformation, pooled seroconversion rates were: HPV16 97.8% (95% CI: 94.9-99.1%; I2 = 89.6%; 15 datasets), HPV18 94.2% (95% CI: 86.1-97.7%; I2 = 95.8%; 13 datasets), HPV6 97.0% (95% CI: 93.7-98.6%; I2 = 66.1%; 10 studies), and HPV11 97.1% (95% CI: 90.5-99.1%; I2 = 95.5%; 10 studies). CD4 count was the most consistently reported modifier of immunogenic response: HPV16 seroconversion was 98.5% in PLWH with CD4 > 350 cells/μL vs. 71.1% in those with CD4 ≤ 200 cells/μL (ACTG A5240). All three vaccine generations demonstrated high immunogenicity. Two doses of the nonavalent vaccine were non-inferior to three doses in virologically suppressed women (Papillon RCT). No vaccine-related serious adverse events were reported. GRADE certainty of evidence was moderate for HPV16, HPV6, and HPV11, and low for HPV18. Prophylactic HPV vaccination achieves high seroconversion rates across all vaccine generations in PLWH. CD4 count significantly modifies vaccine response, underscoring the importance of vaccination before severe immunosuppression develops. These findings support current international recommendations advocating HPV vaccination for all PLWH.

Humans↗

PubMed2026

Hypoxia Response Is Associated with Reduced HPV Activity and Tumor Microenvironment Remodeling in Cervical Cancer.

Human papillomavirus (HPV) significantly influences cervical cancer progression and treatment, yet its interactions with the tumor microenvironment remain incompletely understood. We performed single-cell and spatial transcriptomic sequencing on cervical cancer samples to explore these interactions. By aligning sequencing reads to a merged HPV16-human reference genome, we characterized HPV16 heterogeneity and its association with host states at the single-cell and single-gene levels. E5 transcriptional activity was negatively associated with the host interferon response, indicating a role in immune evasion. A hypoxic environment was correlated with the downregulation of E5 activity and elevated MHC-I expression, which may contribute to stronger interactions between hypoxic cancer cells and cytotoxic CD8⁺ T cells. Additionally, HPV16 integration in host cells was associated with increased fatty acid metabolism. These findings suggest that combining anti-angiogenic drugs and fatty acid metabolism inhibitors has the potential to improve cervical cancer treatment.

Cervical cancer↗

PubMed2026

Lipid reprogramming of stratified squamous epithelium by the high-risk HPV E6 and E6/E7 oncoproteins.

INTRODUCTION: High risk human papillomavirus (HPV) infection and genome integration with pronounced expression of the viral E6/E7 oncogenes is the major cause of cervical cancer. Emerging evidence suggests that HPV reprograms host metabolism to support viral persistence and cellular transformation. However, global HPV oncogene-induced lipidomic reprogramming remains poorly understood, particularly at early stages of HPV-induced transformation. OBJECTIVE: We sought to define the regulation of lipid metabolism in squamous epithelia of transgenic mice expressing the HPV16 oncogene E6 alone or in conjunction with E7. METHODS: Untargeted lipidomics was used to identify novel lipid biomarkers in the skin and female reproductive tract (FRT) of HPV16 E6 and E6/E7 transgenic compared to wild-type (WT) mice. To investigate enzymatic dysregulation of lipids by HPV oncogene expression, we employed Lipid Network Explorer (LINEX2), which analyzes lipidomics data through lipid enrichment analysis. We also used the Global Natural Product Social Molecular Networking (GNPS) platform to enhance lipid identification, exploring molecular networking to improve feature annotation. RESULTS: Our lipidomic analysis produced several new observations. First, E6 expression caused a consistent alteration of glycerophospholipids, with particularly significant substrate-product shifts in the phosphatidylcholine (PC) to lysophosphatidylcholine (LPC) pathway in the skin. Second, E6/E7 expression caused a dysregulation of glucosylceramide (GlcCer) biosynthesis. Third, both E6/E7 expressing skin and FRT tissues exhibited a redox imbalance and increased levels of oxidized lipids, including oxylipins and several oxidized PCs. These findings suggest that HPV oncoproteins drive lipid reprogramming, potentially contributing to early HPV-related tumorigenesis. CONCLUSIONS: These findings provide new insights into HPV‑induced lipid reprogramming and establish a framework for future studies examining the functional and clinical relevance of lipid alterations in HPV‑associated cancers.

Animals↗

PubMed2025

Analytical and clinical performance validation of HPV-SEQ, a novel NGS-based liquid biopsy platform for detection and quantification of human papilloma virus circulating tumor DNA.

BACKGROUND: Human papillomavirus (HPV) is the primary causative driver of oropharyngeal squamous cell carcinoma (OPSCC). Accurate detection of HPV-DNA is critical for risk stratification and management of OPSCC. However, assays designed to detect HPV in primary tumors do not allow monitoring of HPV-DNA over time, whereas commercially available droplet digital PCR-based methods for assessment of circulating cell free (cf)HPV-DNA in plasma remain suboptimal, hindering adaptation into clinical practice. We have developed HPV-SEQ, a novel next-generation-sequencing (NGS) based method for detection and quantification of HPV16/18 DNA in plasma of patients with OPSCC. METHODS: The assay uses primers targeting the L1 gene of HPV16 and HPV18 viral genomes and strain specific calibrators at a defined concentration to determine the ratio of native HPV to a known standard, enabling accurate reporting of patient-derived HPV16/18 viral load in a sample. This study was conducted using two different patient populations in addition to healthy donors and contrived material. All experiments were performed to fulfill several applicable analytical, performance and validation guidelines. RESULTS: A thorough analytical characterization and clinical validation of this platform demonstrates that HPV-SEQ detects cfHPV-DNA with exceptional limit of quantification and high precision, providing a foundation for integrating this platform into clinical settings. CONCLUSIONS: This ultra-sensitive HPV profiling method with optimal analytical performance may represent a significant advancement in risk stratification, treatment management, and post-treatment surveillance for patients with OPSCC.

Humans↗

PubMed2025

Oncoproteins E6/E7 of the human papillomavirus types 16 & 18 synergize in modulating oncogenes and tumor suppressor proteins in colorectal cancer.

OBJECTIVE: Our study presents a novel analysis of the oncogenes and tumor suppressor proteins directly modulated by E6/E7 of high-risk HPV types 16 and 18, in colorectal cancer (CRC). METHODS: HCT 116 (KRAS mutant) & HT-29 (TP53 mutant) cell models of CRC were transduced with E6/E7 of HPV16 and HPV18, individually and in combination. Further, we utilized a liquid chromatography mass spectrometry (LC-MS/MS) approach to analyze and compare the proteomes of both CRC cell models. RESULTS: We generated six stably transduced cell lines. Our data revealed a significantly higher, HPV-induced modulation of oncogenes and tumor suppressor proteins in the TP53 mutant model, as compared to the KRAS mutant model (p ≤ 0.01). Less than 1% of the genes were commonly modulated by HPV, between both models. We also report that HT-29 cells, expressing E6/E7 of both HPV types, significantly reduced the suppression of oncogenes as compared to cells expressing E6/E7 of either HPV types individually (p-value ≤0.00001). CONCLUSION: Our data imply that HPV coinfections leads to the sustenance of a pro-oncogenic environment in CRC. HPV modulates different oncogenes/tumor suppressor proteins in CRC of varying mutational backgrounds, thus highlighting the importance of personalized therapies for such diseases with mutational heterogeneity.

Humans↗

PubMed2025

Serum, Cell-Free, HPV-Human DNA Junction Detection and HPV Typing for Predicting and Monitoring Cervical Cancer Recurrence.

Almost all cervical cancers are caused by human papillomaviruses (HPVs). In most cases, HPV DNA is integrated into the human genome. We found that tumor-specific, HPV-human DNA junctions are detectable in serum cell-free DNA of a fraction of cervical cancer patients at the time of initial treatment and/or at six months following treatment. Retrospective analysis revealed these junctions were more frequently detectable in women in whom the cancer later recurred. We also found that cervical cancers caused by HPV types outside of phylogenetic clade α9 had a higher recurrence frequency than those caused by α9 types in both our study and The Cancer Genome Atlas cervical cancer database, despite the higher prevalence of α9 types including HPV16 in cervical cancer. Thus, HPV-human DNA junction detection in serum cell-free DNA and HPV type determination in tumor tissue may help predict recurrence risk. Screening serum cell-free DNA for junctions may also offer an unambiguous, non-invasive means to monitor absence of recurrence following treatment.

DNA integration↗

PubMed2026

Prevalence and persistence of high-risk HPV genotypes in unvaccinated asymptomatic women: a six-year study in Peru.

OBJECTIVE: This study was to determine the frequency of HPV-hr and describe the distribution by categories (HPV16, HPV18, HPV-hr non16/18) among unvaccinated asymptomatic women in Peru over a 6-year period (2013-2018). In addition, the disease clearance rate is assessed in a percentage of cases. RESULTS: Of the 6,665 samples, 2,240 (33.6%) tested positive for HPV. Among the positive cases, single-genotype infections were caused by HPV-16 (14.8%), followed by HPV-18 (2.2%) and clustered high-risk HPV (HR-HPV) genotypes (66.7%). Multiple HPV-16 infections were more common than HPV-18 infections. In addition, 22 cases (1%) presented with infection with HPV-16, HPV-18, and HR-HPV genotypes. A subset of 116 samples from patients with 1 to 2 years of follow-up was analyzed further. Clearance rates were high, at 68.8% for HPV-16 infections and 67.5% for HR-HPV infections. However, the elimination rate of multiple infections with HPV-16 and HR-HPV genotypes was slightly lower, at 55.6%.

Prevalence↗

PubMed2025

Transcriptomic profile induced by calcitriol in CaSki human cervical cancer cell line.

The vitamin D endocrine system, primarily mediated by its main metabolite calcitriol and the vitamin D receptor (VDR), plays a critical role in numerous human physiological processes, ranging from calcium metabolism to the prevention of various tumors, including cervical cancer. In this study, we comprehensively investigated the genomic regulatory effects of calcitriol in a cervical cancer model. We examined the transcriptional changes induced by calcitriol in CaSki cells, a cervical cell line harboring multiple copies of HPV16, the primary causal agent of cervical cancer. Our microarray findings, revealed that calcitriol regulated over 1000 protein-coding genes, exhibiting a predominantly repressive effect on the CaSki cell transcriptome by suppressing twice as many genes as it induced. Calcitriol decreased EPHA2 and RARA expression while inducing KLK6 and CYP4F3 expression in CaSki cells, as validated by qPCR and Western blot. Functional analysis demonstrated that calcitriol effectively inhibited key processes involved in cancer progression, including cell proliferation and migration. This was further supported by the significant downregulation of MMP7 and MMP13 mRNA levels. Our microarray results also showed that, in addition to its effects on protein-coding genes, calcitriol significantly regulates non-coding RNAs, altering the expression of approximately 400 non-coding RNAs, including 111 microRNA precursors and 29 mature microRNAs, of which 17 were upregulated and 12 downregulated. Notably, among these calcitriol-regulated microRNAs are some involved in cervical cancer biology, such as miR-6129, miR-382, miR-655, miR-211, miR-590, miR-130a, miR-301a, and miR-1252. Collectively, these findings suggest that calcitriol exhibits a significant antitumor effect in this advanced cervical cancer model by blocking critical processes for tumor progression, underscoring the importance of maintaining adequate vitamin D nutritional status.

Humans↗

PubMed2026

Longitudinal analysis of high-risk HPV infections reveals within-host viral genome changes over time.

Persistent infection with high-risk (HR)-HPV causes cervical cancer, however, it is unclear why most infections resolve while a minority progress. We deep sequenced the HPV genomes of 1,228 HR-HPV-positive serial samples from 351 women with persistent infections (2-10 serial samples per woman over 1-8 years), including 279 controls and 72 precancer/cancer cases, to assess HR-HPV genome changes during infection and relation to infection outcomes. Seventy-seven percent of persistent infections (45-97% by HPV type) were infections with the same exact viral genome isolate; for HPV16, only 52% were persistent with the same isolate. This may suggest some infections include a type-specific isolate switch or new isolate infection during persistence. We additionally observed within-host change to the HPV genome estimated as gradual changes to intrahost single nucleotide variant (iSNV) frequency, and changes varied by HPV type, with HPV33 infections showing the most iSNV changes. Cases exhibited fewer viral genome changes during infection compared to controls (OR = 0.31, 95% CI = 0.1 - 0.86, p = 0.019), suggesting a more stable and clonal viral genome in cases. By viral gene, E7 had fewer nonsynonymous mutations in the cases compared to controls that cleared within 2 years of infection (p = 0.012), which confirms the importance of E7 conservation and suggests mutations to E7 reduce persistence associated with progression. There was a similar pattern in E4 (p = 0.013), while E5 had more changes in the cases (p = 0.008). A subset of 28 infections had an intervening HPV-negative sample between HPV-positive visits; 93% of these infections had the same exact viral genome isolate in the samples before and after the negative, consistent with subclinical persistence and subsequent re-detection. Our data suggests that HR-HPV type-persistence can include a collection of viral isolates, and viral mutations during infection, particularly in E7, reduce HR-HPV persistence and thus carcinogenic potential.

Humans↗

PubMed2026

Proteome-wide curation of experimentally validated HPV T-cell epitopes identifies key gaps in our understanding of cellular immunity to HPV and informs vaccine design.

BACKGROUND: Human papillomavirus (HPV) drives both malignant and benign tumours. Current prophylactic vaccines are type-restricted, not optimised for T-cell induction, and lack therapeutic efficacy. Although T-cells are critical for both preventing and clearing HPV infection, experimentally validated HPV T-cell epitopes remain fragmented across the literature, limiting systematic evaluation of cellular immune targets. METHODS: We curated experimentally validated HPV T-cell epitopes from the Immune Epitope Database (IEDB). Epitopes were mapped across HPV proteins and genotypes, and analysed for response rate, sequence conservation across 454 representative HPV genomes, and HLA restriction patterns. RESULTS: 485 unique experimentally validated HPV epitopes have been described (133 studies; 1,494 functional assays). Consistent with research focus and viral biology, E6 and E7 proteins account for >60% of known HPV epitopes despite accounting for ~10% of the viral proteome. High-risk HPV types, especially HPV16 and HPV18, were the most studied (p <.001) and were enriched for CD8+ epitopes (p <.001). We identified major knowledge gaps, including: underrepresentation of structural proteins such as L2; limited epitope coverage for low-prevalence HPV genotypes; a bias towards common HLA alleles. In silico analysis indicated greater conservation of epitopes in L1/L2 and across high-risk HPV types. Conserved, commonly detected, and HLA-promiscuous epitopes were highlighted and we provide panels of candidate epitopes for consideration in immune monitoring, broad-spectrum prophylactic vaccines, and high-risk targeted therapeutic vaccines. CONCLUSION: This study provides the first comprehensive atlas of experimentally validated HPV T-cell epitopes and ranked epitope candidates for translational application. We demonstrate that our understanding of HPV T-cell immunity is constrained by biases in antigen, genotype and HLA focus and by incomplete epitope mapping. Addressing these gaps will be essential for a comprehensive assessment of cellular immunity and for utilising T-cells in next-generation vaccines.

Epitopes, T-Lymphocyte↗

PubMed2025

HPV as a Molecular Hacker: Computational Exploration of HPV-Driven Changes in Host Regulatory Networks.

Human Papillomavirus (HPV), particularly high-risk strains such as HPV16 and HPV18, is a leading cause of cervical cancer and a significant risk factor for several other epithelial malignancies. While the oncogenic mechanisms of viral proteins E6 and E7 are well characterized, the broader effects of HPV infection on host transcriptional regulation remain less clearly defined. This study explores the hypothesis that conserved genomic motifs within the HPV genome may act as molecular decoys, sequestering human transcription factors (TFs) and thereby disrupting normal gene regulation in host cells. Such interactions could contribute to oncogenesis by altering the transcriptional landscape and promoting malignant transformation.We conducted a computational analysis of the genomes of high-risk HPV types using MEME-ChIP for de novo motif discovery, followed by Tomtom for identifying matching human TFs. Protein-protein interactions among the predicted TFs were examined using STRING, and biological pathway enrichment was performed with Enrichr. The analysis identified conserved viral motifs with the potential to interact with host transcription factors (TFs), notably those from the FOX, HOX, and NFAT families, as well as various zinc finger proteins. Among these, SMARCA1, DUX4, and CDX1 were not previously associated with HPV-driven cell transformation. Pathway enrichment analysis revealed involvement in several key biological processes, including modulation of Wnt signaling pathways, transcriptional misregulation associated with cancer, and chromatin remodeling. These findings highlight the multifaceted strategies by which HPV may influence host cellular functions and contribute to pathogenesis. In this context, the study underscores the power of in silico approaches for elucidating viral-host interactions and reveals promising therapeutic targets in computationally predicted regulatory network changes.

Humans↗

PubMed2026

Serum, cell-free, HPV-human DNA junction detection and HPV typing for predicting and monitoring cervical cancer recurrence.

Almost all cervical cancers are caused by human papillomaviruses (HPVs). In most cases, HPV DNA is integrated into the human genome. We found that tumor-specific, HPV-human DNA junctions are detectable in serum cell-free DNA of a fraction of cervical cancer patients at the time of initial treatment and/or at 6 months following treatment. Retrospective analysis revealed these junctions were more frequently detectable in women in whom the cancer later recurred. We also found that cervical cancers caused by HPV types outside of phylogenetic clade α9 had a higher recurrence frequency than those caused by α9 types in both our study and The Cancer Genome Atlas cervical cancer database, despite the higher prevalence ofα9 types, including HPV16, in cervical cancer. Thus, HPV-human DNA junction detection in serum cell-free DNA and HPV type determination in tumor tissue may help predict recurrence risk. Screening serum cell-free DNA for junctions may also offer an unambiguous non-invasive means to monitor absence of recurrence following treatment.

Humans↗