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MBio Feb 2021An unusual feature of papillomaviruses is that their genomes are packaged into virions along with host histones. Viral minichromosomes were visualized as "beads on a...
An unusual feature of papillomaviruses is that their genomes are packaged into virions along with host histones. Viral minichromosomes were visualized as "beads on a string" by electron microscopy in the 1970s but, to date, little is known about the posttranslational modifications of these histones. To investigate this, we analyzed the histone modifications in HPV16/18 quasivirions, wart-derived bovine papillomavirus (BPV1), and wart-derived human papillomavirus type 1 (HPV1) using quantitative mass spectrometry. The chromatin from all three virion samples had abundant posttranslational modifications (acetylation, methylation, and phosphorylation). These histone modifications were verified by acid urea polyacrylamide electrophoresis and immunoblot analysis. Compared to matched host cell controls, the virion minichromosome was enriched in histone modifications associated with active chromatin and depleted for those commonly found in repressed chromatin. We propose that the viral minichromosome acquires specific histone modifications late in infection that are coupled to the mechanisms of viral replication, late gene expression, and encapsidation. We predict that, in turn, these same modifications benefit early stages of infection by helping to evade detection, promoting localization of the viral chromosome to beneficial regions of the nucleus, and promoting early transcription and replication. A relatively unique feature of papillomaviruses is that the viral genome is associated with host histones inside the virion. However, little is known about the nature of the epigenome within papillomavirions or its biological relevance to the infectious viral cycle. Here, we define the epigenetic signature of the H3 and H4 histones from HPV16 virions generated in cell culture and native human papillomavirus type 1 (HPV1) and bovine papillomavirus 1 (BPV1) virions isolated from bovine and human wart tissue. We show that native virions are enriched in posttranslational modifications associated with active chromatin and depleted with those associated with repressed chromatin compared to cellular chromatin. Native virions were also enriched in the histone variant H3.3 compared to the canonical histone H3.1. We propose that the composition of virion-packaged chromatin reflects the late stages of the viral life cycle and promotes the early stages of infection by being primed for viral transcription.
Topics: Animals; Cattle; Chromosomes; HEK293 Cells; Histone Code; Histones; Human papillomavirus 16; Human papillomavirus 18; Humans; Keratinocytes; Methylation; Papillomaviridae; Protein Processing, Post-Translational; Virion; Virus Replication
PubMed: 33593981
DOI: 10.1128/mBio.03274-20 -
Viruses Apr 2022Beta human papillomavirus (beta HPV) infections are common in adults. Certain types of beta HPVs are associated with nonmelanoma skin cancer (NMSC) in immunocompromised... (Review)
Review
Beta human papillomavirus (beta HPV) infections are common in adults. Certain types of beta HPVs are associated with nonmelanoma skin cancer (NMSC) in immunocompromised individuals. However, whether beta HPV infections promote NMSC in the immunocompetent population is unclear. They have been hypothesized to increase genomic instability stemming from ultraviolet light exposure by disrupting DNA damage responses. Implicit in this hypothesis is that the virus encodes one or more proteins that impair DNA repair signaling. Fluorescence-based reporters, next-generation sequencing, and animal models have been used to test this primarily in cells expressing beta HPV E6/E7. Of the two, beta HPV E6 appears to have the greatest ability to increase UV mutagenesis, by attenuating two major double-strand break (DSB) repair pathways, homologous recombination, and non-homologous end-joining. Here, we review this dysregulation of DSB repair and emerging approaches that can be used to further these efforts.
Topics: Alphapapillomavirus; Animals; DNA Repair; Homologous Recombination; Papillomaviridae; Papillomavirus Infections; Skin Neoplasms
PubMed: 35632690
DOI: 10.3390/v14050948 -
Cancer Discovery Apr 2023The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous...
UNLABELLED
The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines identified a previously undescribed form of structural variation, "heterocateny," characterized by diverse, interrelated, and repetitive patterns of concatemerized virus and host DNA segments within a cancer. Unique breakpoints shared across structural variants facilitated stepwise reconstruction of their evolution from a common molecular ancestor. This analysis revealed that virus and virus-host concatemers are unstable and, upon insertion into and excision from chromosomes, facilitate capture, amplification, and recombination of host DNA and chromosomal rearrangements. Evidence of heterocateny was detected in extrachromosomal and intrachromosomal DNA. These findings indicate that heterocateny is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.
SIGNIFICANCE
Long-read sequencing of HPV-positive cancers revealed "heterocateny," a previously unreported form of genomic structural variation characterized by heterogeneous, interrelated, and repetitive genomic rearrangements within a tumor. Heterocateny is driven by unstable concatemerized HPV genomes, which facilitate capture, rearrangement, and amplification of host DNA, and promotes intratumoral heterogeneity and clonal evolution. See related commentary by McBride and White, p. 814. This article is highlighted in the In This Issue feature, p. 799.
Topics: Humans; Human Papillomavirus Viruses; Papillomavirus Infections; Gene Rearrangement; Oropharyngeal Neoplasms; Clonal Evolution; Virus Integration; Papillomaviridae
PubMed: 36715691
DOI: 10.1158/2159-8290.CD-22-0900 -
PeerJ 2023We aimed to estimate the genotype distribution of persistent human papillomavirus (HPV) infection in females worldwide, and provided a scientific basis for the... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
We aimed to estimate the genotype distribution of persistent human papillomavirus (HPV) infection in females worldwide, and provided a scientific basis for the prevention strategies of cervical cancer (CC) and the development of HPV vaccines.
METHODS
Both English and Chinese databases were researched from the inception to July 2023. The pooled persistent HPV infection prevalence was calculated using a random effects model. The subgroup analysis was performed to explore the heterogeneity. Publication bias was evaluated using funnel plot, Egger's and Begg's test.
RESULTS
Twenty-eight studies with 27,335 participants were included. The pooled prevalence of persistent HPV infection was 29.37% (95% CI [24.05%∼35.31%]), and the genotypes with the persistent infection prevalence were HPV16 (35.01%), HPV52 (28.19%), HPV58 (27.06%), HPV18 (25.99%), HPV33 (24.37%), HPV31 (23.35%), HPV59 (21.87%), HPV39 (19.54%), HPV68 (16.61%) and HPV45 (15.05%). The prevalence of multiple and single HPV persistent infection were 48.66% and 36.71%, respectively; the prevalence of persistent HPV infection in different age groups (<30, 30∼39, 40∼49, >50) were 29.83%, 28.39%, 22.24% and 30.22%, respectively. The follow-up time was significantly associated with heterogeneity by subgroup analysis ( < 0.05), and the prevalence of persistent infection decreased with longer follow-up time.
CONCLUSIONS
Multiple infections were more likely to occur persistent HPV infection than single infection. In addition to HPV vaccination, we should emphasize the follow-up management for women under 30 and over 50 years old, those with high-risk HPV infection (HPV59, 39, 68) and multiple infections.
Topics: Female; Humans; Middle Aged; Papillomavirus Infections; Human Papillomavirus Viruses; Persistent Infection; Papillomaviridae
PubMed: 38025679
DOI: 10.7717/peerj.16247 -
The Laryngoscope Dec 2023Laryngeal human papillomavirus (HPV) infection causes recurrent respiratory papillomatosis (RRP) and accounts for up to 25% of laryngeal cancers. Lack of satisfactory... (Review)
Review
OBJECTIVE
Laryngeal human papillomavirus (HPV) infection causes recurrent respiratory papillomatosis (RRP) and accounts for up to 25% of laryngeal cancers. Lack of satisfactory preclinical models is one reason that treatments for these diseases are limited. We sought to assess the literature describing preclinical models of laryngeal papillomavirus infection.
DATA SOURCES
PubMed, Web of Science, and Scopus were searched from the inception of database through October 2022.
REVIEW METHODS
Studies searched were screened by two investigators. Eligible studies were peer-reviewed, published in English, presented original data, and described attempted models of laryngeal papillomavirus infection. Data examined included type of papillomavirus, infection model, and results including success rate, disease phenotype, and viral retention.
RESULTS
After screening 440 citations and 138 full-text studies, 77 studies published between 1923 and 2022 were included. Models used low-risk HPV or RRP (n = 51 studies), high-risk HPV or laryngeal cancer (n = 16), both low- and high-risk HPV (n = 1), and animal papillomaviruses (n = 9). For RRP, 2D and 3D cell culture models and xenografts retained disease phenotypes and HPV DNA in the short term. Two laryngeal cancer cell lines were consistently HPV-positive in multiple studies. Animal laryngeal infections with animal papillomaviruses resulted in disease and long-term retention of viral DNA.
CONCLUSIONS
Laryngeal papillomavirus infection models have been researched for 100 years and primarily involve low-risk HPV. Most models lose viral DNA after a short duration. Future work is needed to model persistent and recurrent diseases, consistent with RRP and HPV-positive laryngeal cancer.
LEVEL OF EVIDENCE
NA Laryngoscope, 133:3256-3268, 2023.
Topics: Humans; Laryngeal Neoplasms; Papillomavirus Infections; DNA, Viral; Larynx; Respiratory Tract Infections; Papillomaviridae; Human papillomavirus 11
PubMed: 37227124
DOI: 10.1002/lary.30762 -
International Journal of Cancer Mar 2024We intended to update human papillomavirus (HPV) prevalence and p16 positivity in oropharyngeal squamous cell carcinomars (SCC), and calculate HPV attributable fraction... (Meta-Analysis)
Meta-Analysis
We intended to update human papillomavirus (HPV) prevalence and p16 positivity in oropharyngeal squamous cell carcinomars (SCC), and calculate HPV attributable fraction (AF) for oropharyngeal SCC by geographic region. We searched Medline, Embase, and the Cochrane Library to identify published studies of HPV prevalence and p16 positivity alone or together in oropharyngeal SCC before December 28, 2021. Studies that reported type-specific HPV DNA prevalence using broad-spectrum PCR-based testing methods were included. We estimated pooled HPV prevalence, type-specific HPV prevalence, and p16 positivity. AF of HPV was calculated by geographic region. One hundred and thirty-four studies including 12 139 cases were included in our analysis. The pooled HPV prevalence estimate for oropharyngeal SCC was 48.1% (95% confidence interval [CI] 43.2-53.0). HPV prevalence varied significantly by geographic region, and the highest HPV prevalence in oropharyngeal SCC was noted in North America (72.6%, 95% CI 63.8-80.6). Among HPV positive cases, HPV 16 was the most common type with a prevalence of 40.2% (95% CI 35.7-44.7). The pooled p16 positivity in HPV positive and HPV16 positive oropharyngeal SCC cases was 87.2% (95% CI 81.6-91.2) and 91.7% (84.3-97.2). The highest AFs of HPV and HPV16 were noted in North America at 69.6% (95% CI 53.0-91.5) and 63.0% (48.0-82.7). [Correction added on 31 October 2023, after first online publication: the percentage symbol (%) was missing and has been added to 63.0% (48.0-82.7) in the Abstract and Conclusion.] A significant proportion of oropharyngeal SCC was attributable to HPV. HPV16 accounts for the majority of HPV positive oropharyngeal SCC cases. These findings highlight the importance of HPV vaccination in the prevention of a substantial proportion of oropharyngeal SCC cases.
Topics: Humans; Carcinoma, Squamous Cell; Cyclin-Dependent Kinase Inhibitor p16; DNA, Viral; Head and Neck Neoplasms; Human papillomavirus 16; Human Papillomavirus Viruses; Oropharyngeal Neoplasms; Papillomaviridae; Papillomavirus Infections; Squamous Cell Carcinoma of Head and Neck
PubMed: 37861207
DOI: 10.1002/ijc.34763 -
Virology Jun 2021We assessed the quality of human papillomavirus (HPV) sequences in GenBank by analyzing the possible presence of chimeras, "wrong-assembled" contigs and errors in...
We assessed the quality of human papillomavirus (HPV) sequences in GenBank by analyzing the possible presence of chimeras, "wrong-assembled" contigs and errors in taxonomy using an open-source script (HPVChimera_Gb) that compared 25 638 HPV-related nucleotide sequences in GenBank with the 221 numbered HPV types and another 220 complete HPV sequences. There were 110 sequences with taxonomy/naming errors (sequences reported as another HPV type than the one they corresponded to) and 1318 possibly chimeric sequences. Manual analysis found plausible explanations for most of them (e.g. sequence covering an integration site) but 114 sequences appeared to be chimeras (96/114 were already flagged as "unverified" by GenBank) and 13 had taxonomy/naming errors. When comparing all correct HPV sequences in GenBank, there appeared to exist about 800 unique putative HPV types. Systematic and regular work towards eliminating chimeric sequences and taxonomy/naming errors could increase the quality and order in HPV research.
Topics: Amino Acid Sequence; Base Sequence; Classification; Databases, Nucleic Acid; Humans; Papillomaviridae
PubMed: 33730650
DOI: 10.1016/j.virol.2021.03.002 -
Veterinary Pathology Nov 2022Nine distinct papillomaviruses (Lambdapapillomavirus) have been described in domestic and nondomestic cats, but not in cheetahs. These viruses have been associated with...
Nine distinct papillomaviruses (Lambdapapillomavirus) have been described in domestic and nondomestic cats, but not in cheetahs. These viruses have been associated with cutaneous papillomas or plaques, bowenoid carcinomas, feline cutaneous squamous cell carcinomas (SCC), feline sarcoids, and oral (often sublingual) papillomas. Fourteen cheetahs from the AfriCat foundation (Namibia) and one from the Ann van Dyk Cheetah center (South Africa) presented with sublingual lesions reminiscent of sublingual papillomas. Two animals were biopsied and the histopathology revealed benign proliferative epithelial lesions with prominent thickening of the overlying squamous epithelium. Throughout the squamous epithelial layers were cells with nuclear enlargement, irregularity of the nuclear membranes and cell contours, focal hyperchromasia of the nuclei, and perinuclear halos, reminiscent of a virus-associated process as seen in papillomavirus infections. Thirteen more cheetahs were sampled and the tissue snap frozen for molecular characterization. Amplification and sequencing of the papillomavirus L1, E6, E7, and E1 gene regions was achieved with modified primers. Maximum likelihood phylogenetic analyses revealed all 15 cheetah papilloma samples were 99.99% genetically similar and closely related to, but genetically distinct from any known felinepapillomaviruses. All cheetahs were FIV and FeLV negative. The results suggest the samples identified in this study can be considered a previously undescribed or novel feline papillomavirus and the authors propose " papillomavirus type 1" (AjPV-1), within the genus (Family: Papillomaviridae).
Topics: Acinonyx; Africa, Southern; Animals; Carcinoma, Squamous Cell; Cat Diseases; Cats; Papilloma; Papillomaviridae; Phylogeny
PubMed: 35815910
DOI: 10.1177/03009858221109610 -
Frontiers in Cellular and Infection... 2022Cervical cancer is the fourth most common cancer in women worldwide. More than 90% of cases are caused by the human papillomavirus (HPV). Vaccines developed only guard... (Review)
Review
Cervical cancer is the fourth most common cancer in women worldwide. More than 90% of cases are caused by the human papillomavirus (HPV). Vaccines developed only guard against a few HPV types and do not protect people who have already been infected. HPV is a small DNA virus that infects the basal layer of the stratified epithelium of the skin and mucosa through small breaks and replicates as the cells differentiate. The mucosal types of HPV can be classified into low-risk and high-risk groups, based on their association with cancer. Among HPV types in high-risk group, HPV type 16 (HPV-16) is the most common, causing 50% of all cancer cases. HPV infection can occur as transient or persistent infections, based on the ability of immune system to clear the virus. Persistent infection is characterized by the integration of HPV genome. HPV-16 exhibits a different integration pattern, with only 50% reported to be integrated at the carcinoma stage. Replication of the HPV genome depends on protein E1, an ATP-dependent helicase. E1 is essential for the amplification of the viral episome in infected cells. Previous studies have shown that E1 does not only act as a helicase protein but is also involved in recruiting and interacting with other host proteins. E1 has also been deemed to drive host cell proliferation. Recent studies have emphasized the emerging role of HPV E1 in cervical carcinogenesis. In this review, a possible mechanism by which E1 drives cell proliferation and oncogenesis will be discussed.
Topics: Carcinogenesis; Cervix Uteri; DNA Helicases; Female; Human papillomavirus 16; Humans; Papillomaviridae; Papillomavirus Infections
PubMed: 35967849
DOI: 10.3389/fcimb.2022.955847 -
Current Opinion in Virology Oct 2021Human papillomaviruses (HPVs) infect and replicate in differentiating mucosal and cutaneous epithelium. Most HPV infections are asymptomatic or cause transient benign... (Review)
Review
Human papillomaviruses (HPVs) infect and replicate in differentiating mucosal and cutaneous epithelium. Most HPV infections are asymptomatic or cause transient benign neoplasia. However, persistent infections by oncogenic HPV types can progress to cancer. During infectious entry into host keratinocytes, HPV particles interact with many host proteins, beginning with major capsid protein L1 binding to cellular heparan sulfate and a series of enzymatic capsid modifications that promote infectious cellular entry. After utilizing the endosomal pathway to uncoat the viral genome (vDNA), the minor capsid protein L2/vDNA complex is retrograde trafficked to the Golgi, and thereafter, to the nucleus where viral transcription initiates. Post-Golgi trafficking is dependent on mitosis, with L2-dependent tethering of vDNA to mitotic chromosomes before accumulation at nuclear substructures in G1. This review summarizes the current knowledge of the HPV entry pathway, the role of cellular proteins in this process, and notes many gaps in our understanding.
Topics: Alphapapillomavirus; Capsid Proteins; Humans; Papillomaviridae; Papillomavirus Infections; Virus Internalization
PubMed: 34416595
DOI: 10.1016/j.coviro.2021.07.010