2026-06-03 | Sublineage-Specific A45S Polymorphism Alters the Biological Function of the Human Papillomavirus 11 E7 Protein.
The E7 oncoprotein of human papillomavirus (HPV) plays a crucial role in viral pathogenesis and replication. Although it is generally highly conserved across HPV genotypes, naturally occurring E7 variants can display functional differences that may affect viral persistence, oncogenic potential, and host cellular responses. The prevalent HPV11 A2 sublineage is characterized by a distinctive amino acid substitution at position 45 (A45S) within the E7 protein. In comparative analyses of transfected primary keratinocytes and HPV-negative cancer cells, we here demonstrate that the A45S substitution enhances the interaction of HPV11 E7 with key cellular targets, including pRb family proteins and PTPN14. A further consequence is an increased ability to target both PTPN14 and pRb family proteins for degradation. Functionally, these differences are exemplified by the S45 variant's enhanced ability to activate E2F-driven gene expression, particularly resulting in elevated mRNA levels of key factors involved in homologous recombination-mediated repair of DNA double-strand breaks, a pathway critical for preserving genomic integrity. Together, these findings indicate that the A45S substitution imparts high-risk-like molecular properties to the low-risk HPV11 E7 oncoprotein. To our knowledge, this is the first report to identify a functionally significant alteration in HPV11 E7 activity resulting from a naturally occurring sequence variation. Understanding the underlying mechanisms could provide new strategies for targeting the therapeutically challenging HPV-associated conditions, such as recurrent respiratory papillomatosis.
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2026-06-02 | Clonal expansion and phenotypic alterations of TCR Vβ3+ T cells in juvenile-onset recurrent respiratory papillomatosis: implications for tumor-associated immunity and chemokine-mediated T-cell trafficking.
Juvenile-onset recurrent respiratory papillomatosis (JORRP) is a rare, human papillomavirus (HPV)-driven pediatric disease characterized by recurring papillomas in the respiratory tract. The contribution of dysregulated T-cell immunity to disease severity remains poorly understood. This study included 97 JORRP patients and 124 controls. Due to sample limitations, downstream analyses, including flow cytometry, TCR, and RNA sequencing, were performed on distinct patient subsets (detailed in Methods). We identified a selective expansion of TCR Vβ3+ T cells, including expanded TRBV28 clonotypes, in patients with aggressive disease. These T cells exhibited heightened cytotoxicity and activation markers, and were enriched in papilloma tissues. Within the tumor microenvironment, gene expression profiling revealed upregulated chemokine signaling pathways (CCR2/CCL7, CXCR6/CXCL16) and key immunosuppressive markers, including PD-L1 and TGF-β1. Our findings demonstrate a tumor-specific clonal expansion and functional alteration of TCR Vβ3+ T cells in JORRP, suggesting these pathways as preliminary targets for further investigation.IMPORTANCEOur study identifies a disease-specific T-cell signature in juvenile-onset recurrent respiratory papillomatosis (JORRP), marked by the clonal expansion of TCR Vβ3+ T cells with distinct TRBV28-dominant clonotypes. These T cells exhibit heightened cytotoxic potential and activation markers but appear functionally constrained within an immunosuppressive tumor microenvironment. Additionally, we discovered a dysregulated chemokine axis (CCR2/CCL7 and CXCR6/CXCL16), which likely facilitates T-cell recruitment, yet fails to sustain their antiviral activity. These findings provide mechanistic insights into why HPV-driven papillomas persist despite immune infiltration. Importantly, our work suggests that targeting TCR Vβ3+ T-cell responses and modulating key chemokine pathways could offer novel immunotherapeutic strategies to restore immune control and reduce disease recurrence in JORRP patients.
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2026-05-09 | The Efficacy and Safety of Systemic Treatment for Managing Recurrent Respiratory Papillomatosis: A Systematic Review and Meta-analysis.
Surgical treatment remains the cornerstone of recurrent respiratory papillomatosis (RRP) management; however, aggressive disease often requires frequent procedures with cumulative morbidity. Contemporary systemic options now include systemic bevacizumab and human papillomavirus (HPV)-specific immunotherapies, with immune checkpoint inhibition under investigation. We systematically reviewed the efficacy and safety of systemic therapies for juvenile- and adult-onset RRP, emphasizing current clinician-relevant treatment options. We comprehensively searched PubMed, Scopus, Web of Science, and the Cochrane Library from inception until January 2026. The included studies evaluated any available systemic treatment for managing adult or juvenile-onset RRP. The main outcomes were complete remission, partial response, and adverse events. All the data analyses were performed using STATA 18 BE. We included 35 studies comprising 925 patients. In juvenile-onset RRP, pooled complete remission with systemic bevacizumab was 60% (95% CI 34-87%), and pooled partial response was 46% (95% CI 21-71%). In adult-onset RRP, pooled complete remission with systemic bevacizumab was 44% (95% CI 26-62%), and pooled partial response was 61% (95% CI 43-79%). The most frequently reported bevacizumab adverse events were hypertension (40%), proteinuria (26%), and epistaxis (22%). HPV-specific immunotherapies (including FDA-approved zopapogene imadenovec-drba [Papzimeos; PRGN-2012] for adults and investigational INO-3107) and PD-1/PD-L1-directed therapies demonstrated encouraging early-phase activity but were too heterogeneous for quantitative pooling. Systemic bevacizumab remains the most mature systemic option with consistent real-world evidence and published dosing guidance. HPV-specific immunotherapy has recently transformed adult RRP management with an FDA-approved, short-course treatment option; ongoing studies will clarify optimal sequencing with bevacizumab and the role of checkpoint inhibition.
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