Pub Date : 2024-12-10DOI: 10.1016/j.tvr.2024.200302
Claire D. James , Rachel L. Lewis , Austin J. Witt , Christiane Carter , Nabiha M. Rais , Xu Wang , Molly L. Bristol
Persistent human papillomavirus (HPV) infection is necessary but insufficient for viral oncogenesis. Additional contributing co-factors, such as immune evasion and viral integration have been implicated in HPV-induced cancer progression. It is widely accepted that HPV + keratinocytes require co-culture with fibroblasts to maintain viral DNA as episomes. How fibroblasts regulate viral episome maintenance is a critical knowledge gap. Here we present comprehensive RNA sequencing and proteomic analysis demonstrating that coculture with fibroblasts is supportive of the viral life cycle, and is confirmatory of previous observations. Novel observations suggest that errors in “cross-talk” between fibroblasts and infected keratinocytes may regulate HPV integration and drive oncogenic progression. Our co-culture models offer new insights into HPV-related transformation mechanisms.
{"title":"Fibroblasts regulate the transcriptional signature of human papillomavirus-positive keratinocytes","authors":"Claire D. James , Rachel L. Lewis , Austin J. Witt , Christiane Carter , Nabiha M. Rais , Xu Wang , Molly L. Bristol","doi":"10.1016/j.tvr.2024.200302","DOIUrl":"10.1016/j.tvr.2024.200302","url":null,"abstract":"<div><div>Persistent human papillomavirus (HPV) infection is necessary but insufficient for viral oncogenesis. Additional contributing co-factors, such as immune evasion and viral integration have been implicated in HPV-induced cancer progression. It is widely accepted that HPV + keratinocytes require co-culture with fibroblasts to maintain viral DNA as episomes. How fibroblasts regulate viral episome maintenance is a critical knowledge gap. Here we present comprehensive RNA sequencing and proteomic analysis demonstrating that coculture with fibroblasts is supportive of the viral life cycle, and is confirmatory of previous observations. Novel observations suggest that errors in “cross-talk” between fibroblasts and infected keratinocytes may regulate HPV integration and drive oncogenic progression. Our co-culture models offer new insights into HPV-related transformation mechanisms.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"19 ","pages":"Article 200302"},"PeriodicalIF":4.7,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11699615/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142819715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 10.1016/j.tvr.2024.200300
Maya K. Gelbard , Miranda Grace , Annika von Schoeler-Ames , Ida Gnanou , Karl Munger
Human papillomaviruses (HPVs) are a diverse family of viruses with over 450 members that have been identified and fully sequenced. They are classified into five phylogenetic genera: alpha, beta, gamma, mu, and nu. The high-risk alpha HPVs, such as HPV16, have been studied the most extensively due to their medical significance as cancer-causing agents. However, while nearly 70% of all HPVs are members of the gamma genus, they are almost entirely unstudied. This is because gamma HPVs have been considered medically irrelevant commensals as most of them infect the skin and are not known to cause significant clinical lesions in immunocompetent individuals. Members of the gamma 6 HPVs, however, have been detected in the anogenital tract mucosa and HPV101 has been isolated from a premalignant cervical lesion. Moreover, gamma 6 HPVs have a unique genome structure. They lack E6 proteins but in place of E6, they encode unique, small hydrophobic proteins without any close viral or cellular homologs that have been termed E10. Here, we report that HPV101 E7 shares biochemical activities with the high-risk alpha HPV16 E7, including the ability to target the pRB and PTPN14 tumor suppressors for degradation. This study underscores the importance of further characterizing HPV101 and other unstudied HPV species.
{"title":"The HPV101 E7 protein shares host cellular targets and biological activities with high-risk HPV16 E7","authors":"Maya K. Gelbard , Miranda Grace , Annika von Schoeler-Ames , Ida Gnanou , Karl Munger","doi":"10.1016/j.tvr.2024.200300","DOIUrl":"10.1016/j.tvr.2024.200300","url":null,"abstract":"<div><div>Human papillomaviruses (HPVs) are a diverse family of viruses with over 450 members that have been identified and fully sequenced. They are classified into five phylogenetic genera: alpha, beta, gamma, mu, and nu. The high-risk alpha HPVs, such as HPV16, have been studied the most extensively due to their medical significance as cancer-causing agents. However, while nearly 70% of all HPVs are members of the gamma genus, they are almost entirely unstudied. This is because gamma HPVs have been considered medically irrelevant commensals as most of them infect the skin and are not known to cause significant clinical lesions in immunocompetent individuals. Members of the gamma 6 HPVs, however, have been detected in the anogenital tract mucosa and HPV101 has been isolated from a premalignant cervical lesion. Moreover, gamma 6 HPVs have a unique genome structure. They lack E6 proteins but in place of E6, they encode unique, small hydrophobic proteins without any close viral or cellular homologs that have been termed E10. Here, we report that HPV101 E7 shares biochemical activities with the high-risk alpha HPV16 E7, including the ability to target the pRB and PTPN14 tumor suppressors for degradation. This study underscores the importance of further characterizing HPV101 and other unstudied HPV species.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"19 ","pages":"Article 200300"},"PeriodicalIF":4.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11714379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-05DOI: 10.1016/j.tvr.2024.200301
Lavinia Ghiani, Susanna Chiocca
Understanding the role of NSD proteins in virus-induced cancers could reveal new therapeutic strategies. Targeting NSD proteins may not only disrupt the epigenetic changes triggered by viruses but also help restore normal cellular function. For instance, developing NSD inhibitors could counteract abnormal histone modifications caused by viral infections and slow cancer progression. Our review on the NSD protein family emphasizes its critical role in epigenetic regulation and cancer progression, also in virus-induced cancers. As research on the molecular mechanisms of NSD proteins advances, these proteins are emerging as promising candidates for targeted cancer therapies, particularly in cancers driven by histone modifications and transcriptional dysregulation.
{"title":"The oncogenic role of the NSD histone methyltransferases in head and neck and cervical cancers","authors":"Lavinia Ghiani, Susanna Chiocca","doi":"10.1016/j.tvr.2024.200301","DOIUrl":"10.1016/j.tvr.2024.200301","url":null,"abstract":"<div><div>Understanding the role of NSD proteins in virus-induced cancers could reveal new therapeutic strategies. Targeting NSD proteins may not only disrupt the epigenetic changes triggered by viruses but also help restore normal cellular function. For instance, developing NSD inhibitors could counteract abnormal histone modifications caused by viral infections and slow cancer progression. Our review on the NSD protein family emphasizes its critical role in epigenetic regulation and cancer progression, also in virus-induced cancers. As research on the molecular mechanisms of NSD proteins advances, these proteins are emerging as promising candidates for targeted cancer therapies, particularly in cancers driven by histone modifications and transcriptional dysregulation.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"19 ","pages":"Article 200301"},"PeriodicalIF":4.7,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11683330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142792704","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01DOI: 10.1016/j.tvr.2024.200298
Renato Biffi , Stefanie W. Benoit , Ilker K. Sariyer , Mahmut Safak
The early coding region of JC virus (JCV) encodes several regulatory proteins including large T antigen (LT-Ag), small t antigen (Sm t-Ag) and T’ proteins because of the alternative splicing of the pre-mRNA. LT-Ag plays a critical role in cell transformation by targeting the key cell cycle regulatory proteins including p53 and pRb, however, the role of Sm t-Ag in this process remains elusive. Here, we investigated the effect of Sm t-Ag on the cell cycle progression and demonstrated that it facilitates S phase entry and exit when cells are released from G0/G1 growth arrest. Examination of the cell cycle stage specific expression profiles of the selected cyclins and cyclin-dependent kinases, including those active at the G1/S and G2/M transition state, demonstrated a higher level of early expression of these regulators such as cyclin B, cycling E, and Cdk2. In addition, analysis of the effect of Sm t-Ag on the growth promoting pathways including those active in the PI3K/Akt/mTOR axis showed substantially higher levels of the phosphorylated-Akt, -Gsk3-β and -S6K1 in Sm t-Ag-positive cells. Collectively, our results demonstrate that Sm t-Ag promotes cell cycle progression by activating the growth promoting pathways through which it may contribute to LT-Ag-mediated cell transformation.
JC 病毒（JCV）的早期编码区编码多种调节蛋白，包括大 T 抗原（LT-Ag）、小 T 抗原（Sm t-Ag）和 T'蛋白，这是因为前核糖核酸（pre-mRNA）发生了交替剪接。LT-Ag 通过靶向包括 p53 和 pRb 在内的关键细胞周期调控蛋白，在细胞转化过程中发挥着关键作用。在这里，我们研究了 Sm t-Ag 对细胞周期进展的影响，并证明当细胞从 G0/G1 生长停滞释放时，它能促进 S 期的进入和退出。对选定的细胞周期蛋白和细胞周期蛋白依赖性激酶（包括那些在 G1/S 和 G2/M 过渡状态下活跃的细胞周期蛋白和细胞周期蛋白依赖性激酶）的细胞周期阶段特异性表达谱的研究表明，这些调节因子（如细胞周期蛋白 B、细胞周期蛋白 E 和 Cdk2）的早期表达水平较高。此外，Sm t-Ag 对促进生长通路（包括在 PI3K/Akt/mTOR 轴中活跃的通路）的影响分析表明，Sm t-Ag 阳性细胞中磷酸化-Akt、-Gsk3-β 和 -S6K1 的水平大幅提高。总之，我们的研究结果表明，Sm t-Ag通过激活促进生长的途径来促进细胞周期的进展，它可能通过这些途径促进LT-Ag介导的细胞转化。
{"title":"JC virus small tumor antigen promotes S phase entry and cell cycle progression","authors":"Renato Biffi , Stefanie W. Benoit , Ilker K. Sariyer , Mahmut Safak","doi":"10.1016/j.tvr.2024.200298","DOIUrl":"10.1016/j.tvr.2024.200298","url":null,"abstract":"<div><div>The early coding region of JC virus (JCV) encodes several regulatory proteins including large T antigen (LT-Ag), small t antigen (Sm t-Ag) and T’ proteins because of the alternative splicing of the pre-mRNA. LT-Ag plays a critical role in cell transformation by targeting the key cell cycle regulatory proteins including p53 and pRb, however, the role of Sm t-Ag in this process remains elusive. Here, we investigated the effect of Sm t-Ag on the cell cycle progression and demonstrated that it facilitates S phase entry and exit when cells are released from G0/G1 growth arrest. Examination of the cell cycle stage specific expression profiles of the selected cyclins and cyclin-dependent kinases, including those active at the G1/S and G2/M transition state, demonstrated a higher level of early expression of these regulators such as cyclin B, cycling E, and Cdk2. In addition, analysis of the effect of Sm t-Ag on the growth promoting pathways including those active in the PI3K/Akt/mTOR axis showed substantially higher levels of the phosphorylated-Akt, -Gsk3-β and -S6K1 in Sm t-Ag-positive cells. Collectively, our results demonstrate that Sm t-Ag promotes cell cycle progression by activating the growth promoting pathways through which it may contribute to LT-Ag-mediated cell transformation.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"18 ","pages":"Article 200298"},"PeriodicalIF":4.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142717194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13DOI: 10.1016/j.tvr.2024.200297
June See Chong, John Doorbar
Highly conserved signalling pathways such as Notch and Wnt are essential in the regulation of differentiation and proliferation processes during adult tissue homeostasis. Human papillomaviruses (HPVs) have evolved with humans to manipulate these signalling pathways to establish a basal reservoir of infected cells by limiting HPV-infected keratinocyte differentiation whilst ensuring that differentiating cells are in a replication-competent state. Here, we focus on the canonical Notch and Wnt signalling pathways and their crosstalk to ensure cell-fate lineage determination during epithelial homeostasis. We then examine how HPVs use their E6 and E7 proteins to inhibit differentiation and maintain stem-like characteristics using Notch and Wnt in HPV-infected cells. Determining the functions of E6 and E7 in the maintenance of the infected cell reservoir, and the molecular crosstalk between Notch and Wnt is vital for our understanding of HPV persistence, and may represent an important factor in the development of therapeutic agents for HPV-associated disease.
{"title":"Modulation of epithelial homeostasis by HPV using Notch and Wnt","authors":"June See Chong, John Doorbar","doi":"10.1016/j.tvr.2024.200297","DOIUrl":"10.1016/j.tvr.2024.200297","url":null,"abstract":"<div><div>Highly conserved signalling pathways such as Notch and Wnt are essential in the regulation of differentiation and proliferation processes during adult tissue homeostasis. Human papillomaviruses (HPVs) have evolved with humans to manipulate these signalling pathways to establish a basal reservoir of infected cells by limiting HPV-infected keratinocyte differentiation whilst ensuring that differentiating cells are in a replication-competent state. Here, we focus on the canonical Notch and Wnt signalling pathways and their crosstalk to ensure cell-fate lineage determination during epithelial homeostasis. We then examine how HPVs use their E6 and E7 proteins to inhibit differentiation and maintain stem-like characteristics using Notch and Wnt in HPV-infected cells. Determining the functions of E6 and E7 in the maintenance of the infected cell reservoir, and the molecular crosstalk between Notch and Wnt is vital for our understanding of HPV persistence, and may represent an important factor in the development of therapeutic agents for HPV-associated disease.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"18 ","pages":"Article 200297"},"PeriodicalIF":4.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-08DOI: 10.1016/j.tvr.2024.200296
Harry Scott , Patricia E. Martin , Sheila V. Graham
Connexins are essential for intercellular communication through gap junctions and the maintenance of cellular and tissue homeostasis. Connexin 43 (Cx43) is the most ubiquitously expressed connexin. As well as regulating homeostasis, Cx43 hemichannels and gap junctions play important roles in inflammation and the immune response. This, coupled with a range of non-channel functions performed by Cx43 makes it an attractive target for viruses. Recently, several groups have begun to explore the relationship between Cx43 and viral infection, with a diverse array of viruses being found to alter Cx43 hemichannels/gap junctions. Importantly, this includes several small DNA tumour viruses, which may target Cx43 to promote tumorigenesis. This review focuses on the ability of selected RNA/DNA viruses and retroviruses to either positively or negatively regulate Cx43 hemichannels and gap junctions in order to carry out their lifecycles. The role of Cx43 regulation by tumour viruses is also discussed in relation to tumour progression.
{"title":"Modulation of connexin 43 in viral infections","authors":"Harry Scott , Patricia E. Martin , Sheila V. Graham","doi":"10.1016/j.tvr.2024.200296","DOIUrl":"10.1016/j.tvr.2024.200296","url":null,"abstract":"<div><div>Connexins are essential for intercellular communication through gap junctions and the maintenance of cellular and tissue homeostasis. Connexin 43 (Cx43) is the most ubiquitously expressed connexin. As well as regulating homeostasis, Cx43 hemichannels and gap junctions play important roles in inflammation and the immune response. This, coupled with a range of non-channel functions performed by Cx43 makes it an attractive target for viruses. Recently, several groups have begun to explore the relationship between Cx43 and viral infection, with a diverse array of viruses being found to alter Cx43 hemichannels/gap junctions. Importantly, this includes several small DNA tumour viruses, which may target Cx43 to promote tumorigenesis. This review focuses on the ability of selected RNA/DNA viruses and retroviruses to either positively or negatively regulate Cx43 hemichannels and gap junctions in order to carry out their lifecycles. The role of Cx43 regulation by tumour viruses is also discussed in relation to tumour progression.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"18 ","pages":"Article 200296"},"PeriodicalIF":4.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142632420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.tvr.2024.200295
Malay K. Sannigrahi , Lovely Raghav , Ahmed Diab , Devraj Basu
Human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) are variable in their progression, immune landscape, treatment responses, and clinical outcomes. Their behavior is impacted not only by differences in host genomic alterations but also by diversity in levels and activity of HPV-encoded oncoproteins. Striking differences in HPV mRNA levels are found among HPV+ OPSCCs and likely derive in part from variations in the structurally diverse mix of integrated and episomal HPV genomes they often contain. Viral oncoprotein levels and function are also impacted by differential splicing of the two long polycistronic transcripts of HPV16, the HPV type within most HPV+ OPSCCs. Further variation in viral oncoprotein function arises from the distinct lineages and sub-lineages of HPV16, which encode polymorphisms in functionally important portions of oncogenes. Here we review the limited current knowledge linking HPV mRNA expression and splicing to differences in oncoprotein function that likely influence OPSCC behavior. We also summarize the evolving understanding of HPV16 physical genome state and genetic variants and their potential contributions to HPV oncoprotein levels and function. Addressing considerable remaining challenges in defining the quantitative and qualitative imprint of HPV oncoproteins on each OPSCC holds promise to guide personalization of therapy for this disease.
{"title":"The imprint of viral oncoproteins on the variable clinical behavior among human papilloma virus-related oropharyngeal squamous cell carcinomas","authors":"Malay K. Sannigrahi , Lovely Raghav , Ahmed Diab , Devraj Basu","doi":"10.1016/j.tvr.2024.200295","DOIUrl":"10.1016/j.tvr.2024.200295","url":null,"abstract":"<div><div>Human papilloma virus-related (HPV+) oropharyngeal squamous cell carcinomas (OPSCCs) are variable in their progression, immune landscape, treatment responses, and clinical outcomes. Their behavior is impacted not only by differences in host genomic alterations but also by diversity in levels and activity of HPV-encoded oncoproteins. Striking differences in HPV mRNA levels are found among HPV+ OPSCCs and likely derive in part from variations in the structurally diverse mix of integrated and episomal HPV genomes they often contain. Viral oncoprotein levels and function are also impacted by differential splicing of the two long polycistronic transcripts of HPV16, the HPV type within most HPV+ OPSCCs. Further variation in viral oncoprotein function arises from the distinct lineages and sub-lineages of HPV16, which encode polymorphisms in functionally important portions of oncogenes. Here we review the limited current knowledge linking HPV mRNA expression and splicing to differences in oncoprotein function that likely influence OPSCC behavior. We also summarize the evolving understanding of HPV16 physical genome state and genetic variants and their potential contributions to HPV oncoprotein levels and function. Addressing considerable remaining challenges in defining the quantitative and qualitative imprint of HPV oncoproteins on each OPSCC holds promise to guide personalization of therapy for this disease.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"18 ","pages":"Article 200295"},"PeriodicalIF":4.7,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-29DOI: 10.1016/j.tvr.2024.200294
Massilva Rahmoun , Audrey Aussel , Sarah Bouzidi , Vincent Pedergnana , Victor Malassigné , Julien Puech , David Veyer , Hélène Péré , Charles Lepine , Fabian Blanc , Nathalie Boulle , Valérie Costes-Martineau , Ignacio G. Bravo
Recurrent respiratory papillomatosis (RRP) is a rare, proliferative disease caused by human papillomavirus 6 (HPV6) and HPV11. RRP can occasionally spread and undergo malignant transformation.
We analysed samples across time for five RRP patients with malignant transformation and four with highly recurrent, non-malignant RRP by applying high-throughput sequencing.
Patients with malignant transformation were infected by HPV11_A1/A2, while most non-malignant cases were associated with HPV6. Transient multiple infections with HPV6 and HPV11 were found in two patients, and resolved later to single infections. Viral genome loads were homogeneous across groups (median = 78 viral genomes per human genome). Within-patient, we did not observe differences between the viral sequences in the papillomatous lesions and in the malignant tissue. Genetic analysis of the NLRP1 gene revealed no known mutations linked to idiopathic RRP, though some novel variants merit to be explored in larger cohorts.
HPV11 infections appear associated with RRP malignant transformation in young patients. Multiple infections can occur in RRP, but within-patient viral diversity is minimal for a given genotype. Our results confirm the importance of viral genotype in disease prognosis and are consistent with growing evidence of HPV11 infections to be differentially associated with RRP malignant transformation in young patients.
{"title":"Genomic diversity of HPV6 and HPV11 in recurrent respiratory papillomatosis: Association with malignant transformation in the lungs and clinical outcomes","authors":"Massilva Rahmoun , Audrey Aussel , Sarah Bouzidi , Vincent Pedergnana , Victor Malassigné , Julien Puech , David Veyer , Hélène Péré , Charles Lepine , Fabian Blanc , Nathalie Boulle , Valérie Costes-Martineau , Ignacio G. Bravo","doi":"10.1016/j.tvr.2024.200294","DOIUrl":"10.1016/j.tvr.2024.200294","url":null,"abstract":"<div><div>Recurrent respiratory papillomatosis (RRP) is a rare, proliferative disease caused by human papillomavirus 6 (HPV6) and HPV11. RRP can occasionally spread and undergo malignant transformation.</div><div>We analysed samples across time for five RRP patients with malignant transformation and four with highly recurrent, non-malignant RRP by applying high-throughput sequencing.</div><div>Patients with malignant transformation were infected by HPV11_A1/A2, while most non-malignant cases were associated with HPV6. Transient multiple infections with HPV6 and HPV11 were found in two patients, and resolved later to single infections. Viral genome loads were homogeneous across groups (median = 78 viral genomes per human genome). Within-patient, we did not observe differences between the viral sequences in the papillomatous lesions and in the malignant tissue. Genetic analysis of the <em>NLRP1</em> gene revealed no known mutations linked to idiopathic RRP, though some novel variants merit to be explored in larger cohorts.</div><div>HPV11 infections appear associated with RRP malignant transformation in young patients. Multiple infections can occur in RRP, but within-patient viral diversity is minimal for a given genotype. Our results confirm the importance of viral genotype in disease prognosis and are consistent with growing evidence of HPV11 infections to be differentially associated with RRP malignant transformation in young patients.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"18 ","pages":"Article 200294"},"PeriodicalIF":4.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-28DOI: 10.1016/j.tvr.2024.200293
Filip Šenigl , Anni I. Soikkeli , Salomé Prost , David G. Schatz , Martina Slavková , Jiří Hejnar , Jukka Alinikula
Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 LT. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to LT is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.
{"title":"The SV40 virus enhancer functions as a somatic hypermutation-targeting element with potential tumorigenic activity","authors":"Filip Šenigl , Anni I. Soikkeli , Salomé Prost , David G. Schatz , Martina Slavková , Jiří Hejnar , Jukka Alinikula","doi":"10.1016/j.tvr.2024.200293","DOIUrl":"10.1016/j.tvr.2024.200293","url":null,"abstract":"<div><div>Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 <em>LT</em>. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 <em>LT</em> in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to <em>LT</em> is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.</div></div>","PeriodicalId":52381,"journal":{"name":"Tumour Virus Research","volume":"18 ","pages":"Article 200293"},"PeriodicalIF":4.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142560626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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