Search

A massive mortality event concerning farmed Chinese tongue soles occurred in Tianjin, China, and the causative agent remains unknown. Here, a novel Cynoglossus semilaevis papillomavirus (CsPaV) and parvovirus (CsPV) were simultaneously isolated and identified from diseased fish via electron microscopy, virus isolation, genome sequencing, experimental challenges, and fluorescence in situ hybridization (FISH). Electron microscopy showed large numbers of virus particles present in the tissues of diseased fish. Viruses that were isolated and propagated in flounder gill cells (FG) induced typical cytopathic effects (CPE). The cumulative mortality of fish given intraperitoneal injections reached 100% at 7 dpi. The complete genomes of CsPaV and CsPV comprised 5939 bp and 3663 bp, respectively, and the genomes shared no nucleotide sequence similarities with other viruses. Phylogenetic analysis based on the L1 and NS1 protein sequences revealed that CsPaV and CsPV were novel members of the Papillomaviridae and Parvoviridae families. The FISH results showed positive signals in the spleen tissues of infected fish, and both viruses could co-infect single cells. This study represents the first report where novel papillomavirus and parvovirus are identified in farmed marine cultured fish, and it provides a basis for further studies on the prevention and treatment of emerging viral diseases. [ABSTRACT FROM AUTHOR]

Domestic dogs are currently recognized as being infected by 25 different canine papillomavirus (CPV) types classified into three genera. A short sequence from a novel CPV type was amplified, along with CPV1, from a papilloma (wart) from the mouth of a dog. The entire 7499 bp genome was amplified, and CPV26 contained putative coding regions that were predicted to produce four early proteins and two late ones. The ORF L1 showed less than 62% similarity for all previously sequenced CPV types but over 69% similarity to multiple Omegapapillomavirus types from a variety of Caniform species including the giant panda, Weddel seal, and polar bear. Phylogenetic analysis confirmed CPV26 clusters within the Omegapapillomavirus genus. Specific primers were used to investigate the presence of CPV26 DNA within a series of 37 canine proliferative lesions. CPV26 DNA was amplified from one lesion, a cutaneous papilloma that also contained CPV6. This is the first time a PV type within the Omegapapillomavirus genus has been detected in a non-domestic species and this provides evidence that the omegapapillomaviruses infected a common ancestor of, and then co-evolved with, the Caniform species. Whether CPV26 causes disease is uncertain, but the absence of an E7 protein may suggest low pathogenicity. [ABSTRACT FROM AUTHOR]

Simple Summary: The human papillomavirus (HPV), a major carcinogenic pathogen, can cause cervical cancer through persistent infection. The immune system typically fights off the virus, albeit long-term activation may promote carcinogenesis. The micro-immunotherapy medicine 2LPAPI® holds promise for aiding viral clearance and mitigating cervical cancer risk, and our research aimed to examine the effects of this medicine in vitro. We focused our investigations on the two most prevalent genotypes of HPV causing persistent infection, HPV-16 and HPV-18. We found that 2LPAPI® boosted the secretion of IL-6, IFN-γ, and IP-10 in human immune cells when exposed to HPV-16 proteins, suggesting enhanced defensive responses to HPV-16. Some of the active substances curtailed T-cell proliferation and activity and displayed antiproliferative properties on HPV-18 positive cervical cancer-derived HeLa cells in nutrient-restricted conditions. These results unveil 2LPAPI®'s potential dual role: immunomodulation for HPV-16-affected immune cells and antiproliferative activity against a model of HPV-18-positive-cervical cancer cells. Human papillomavirus (HPV) is the second most common infectious agent causing cancer. Persistent infection with high-risk (HR)-HPV can lead to cervical intra-epithelial neoplasia and cervical carcinomas (CC). While host immune response is necessary for viral clearance, chronic immune activation contributes to a low-grade inflammation that can ultimately lead to carcinogenesis. The micro-immunotherapy medicine (MIM) 2LPAPI® could be a valuable tool to manage the clearance of the virus and reduce the risk of developing CC. In this in vitro study, we aimed to investigate its mode of action. We showed that actives from the MIM increased the IL-6, IFN-γ, and IP-10 secretion in human peripheral blood mononuclear cells (PBMCs) exposed to peptides derived from the HPV-16 capsid (HPV16(L1)). This could reflect an increase in the immune activity toward HPV-16. At the same time, some active substances reduced the lympho-proliferation and the expression of T-cell activation markers. Finally, some of the MIM actives displayed antiproliferative effects in CC-derived HeLa cells under serum-starvation conditions. Altogether, this body of data highlighted for the first time the dual effect of MIM in the framework of HR-HPV infections as a potential (i) immune modulator of HPV16(L1)-treated PBMCs and (ii) antiproliferative agent of HPV-positive CC cells. [ABSTRACT FROM AUTHOR]

Introduction: Human Papillomavirus (HPV) with small size and double-stranded DNA is the most important cause of sexually transmitted infections and cervical carcinoma. Controlling the spread of papillomavirus infection and protecting people against the pathogenicity of this virus are key steps in reducing the number of cervical cancer patients. One of the effective ways to achieve this goal is to design a suitable vaccine. In the present study, computer-aided methods were used to suggest a potential vaccine candidate against HPV. Methods: Oncoproteins L1 and E5 of the high-risk strain HPV 16 were utilized to predict the linear B-cell epitopes, cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL) epitopes. From the obtained epitopes, non-allergenic and non-toxic peptides with acceptable antigenicity were selected and subsequently converted into 3D structures. The epitopes were subjected to molecular docking using the PDB format. In the next step, short amino acid sequences as spacers were used to join peptides together. Finally, computational analysis including allergenicity and antigenicity studies, physicochemical properties, secondary and tertiary structure prediction, molecular interaction pattern, and cloning analyses were conducted for the vaccine construct. Results: Our findings revealed that the designed vaccine with suitable antigenicity and physicochemical properties, shows proper interaction with four types of Toll-like receptors (TLR3, TLR4, TLR5, and TLR8), and Escherichia coli (strain K12) is the suitable host for it. Conclusion: Overall, the vaccine designed in the present study showed a promising immune response. However, further validation through laboratory investigations is required. [ABSTRACT FROM AUTHOR]

Nanotechnology products such as titanium dioxide nanoparticles (TiO2-NPs) can be used for viral infections because of their unique characteristics. The current study aimed to determine the impact of TiO2-NPs on HPV type 1 and 2 infections. The characterization of these NPs was performed using dynamic light scattering (DLS), field emission scanning electron microscopy (FESEM), high-resolution transmission electron microscopy (HRTEM), and X-ray diffraction (XRD). The MTT assay was used to determine the toxic impacts of TiO2-NPs on BHK-21 cells. The efficiency of TiO2-NPs was performed using several parameters, including TCID50 and RT-PCR assays. An indirect immunofluorescence assay (IFA) was performed to estimate the inhibitory impact of TiO2-NPs on viral antigen expression, and Acyclovir was used as a reference medicine. When the human papilloma type 1 and 2 viruses exposed to TiO2-NPs at high doses (100 μg/mL) produced 0.3, 1.1, 2.3, and 3.3 log10 TCID50 decreases in infective virus load when compared with control viruses (P<0.0001), these TiO2-NPs doses were related to 24.9%, 35.1%, 47.2%, 59.5%, and 66.6% inhibition percentages that were determined depending on the viral titer as compared to virus control. It is concluded that TiO2-NPs have strong potential for the treatment of face and labial lesions caused by papillomaviruses 1 and 2 and could be used in topical formulations. [ABSTRACT FROM AUTHOR]

The objective of this study was to assess the occurrence and seasonal frequency of human adenovirus (HAdV), human polyomavirus (HPyV), and human papillomavirus (HPV) in urban sewage. The detection of these viruses was carried out by polymerase chain reaction (PCR), and then the viral concentrations in the positive samples were quantified by quantitative PCR (qPCR). Additionally, HAdV and HPyV genotyping was also performed by PCR. A total of 38/60 (63.3%) positive samples were found. HAdV was the most prevalent virus (26/60; 43.3%), followed by HPyV (21/60; 35%) and HPV (21/60; 35%). The viral concentrations ranged from 3.56× 10² to 7.55 × 107 genome copies/L. The most common dual viral agents was found between HAdV and HPyV, in eight samples (8/38, 21%). HAdV types 40 and 41 as well as HPyV types JC and BK were identified, with HAdV-40 and HPyV JC being the most prevalent types. Furthermore, the detection rates of HAdV, HPyV, and HPV were higher during the winter season than the other seasons. The high prevalence of HAdV and HPyV supports their suitability as viral indicators of sewage contamination. Furthermore, this study demonstrates the advantages of environmental surveillance as a tool to elucidate the community-circulating viruses. [ABSTRACT FROM AUTHOR]

The human papillomavirus (HPV) oncoprotein E7 is a relatively short-lived protein required for HPV-driven cancer development and maintenance. E7 is degraded through ubiquitination mediated by cullin 1 (CUL1) and the ubiquitin-conjugating enzyme E2 L3 (UBE2L3). However, E7 proteins are maintained at high levels in most HPV-positive cancer cells. A previous proteomics study has shown that UBE2L3 and CUL1 protein levels are increased by the knockdown of the E3 ubiquitin ligase membraneassociated ring-CH-type finger 8 (MARCHF8). We have recently demonstrated that HPV16 upregulates MARCHF8 expression in HPV-positive keratinocytes and head and neck cancer (HPV+ HNC) cells. Here, we report that MARCHF8 stabilizes the HPV16 E7 protein by degrading the components of the S-phase kinase-associated protein 1-CUL1-F-box ubiquitin ligase complex in HPV+ HNC cells. We found that MARCHF8 knockdown in HPV+ HNC cells drastically decreases the HPV16 E7 protein level while increasing the CUL1 and UBE2L3 protein levels. We further revealed that the MARCHF8 protein binds to and ubiquitinates CUL1 and UBE2L3 proteins and that MARCHF8 knockdown enhances the ubiquitination of the HPV16 E7 protein. Conversely, the overexpression of CUL1 and UBE2L3 in HPV+ HNC cells decreases HPV16 E7 protein levels and suppresses tumor growth in vivo. Our findings suggest that HPV-induced MARCHF8 prevents the degradation of the HPV16 E7 protein in HPV+ HNC cells by ubiquitinating and degrading CUL1 and UBE2L3 proteins. IMPORTANCE Since human papillomavirus (HPV) oncoprotein E7 is essential for virus replication; HPV has to maintain high levels of E7 expression in HPV-infected cells. However, HPV E7 can be efficiently ubiquitinated by a ubiquitin ligase and degraded by proteasomes in the host cell. Mechanistically, the E3 ubiquitin ligase complex cullin 1 (CUL1) and ubiquitin-conjugating enzyme E2 L3 (UBE2L3) components play an essential role in E7 ubiquitination and degradation. Here, we show that the membrane ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8) induced by HPV16 E6 stabilizes the E7 protein by degrading CUL1 and UBE2L3 and blocking E7 degradation through proteasomes. MARCHF8 knockout restores CUL1 and UBE2L3 expression, decreasing E7 protein levels and inhibiting the proliferation of HPV-positive cancer cells. Additionally, overexpression of CUL1 or UBE2L3 decreases E7 protein levels and suppresses in vivo tumor growth. Our results suggest that HPV16 maintains high E7 protein levels in the host cell by inducing MARCHF8, which may be critical for cell proliferation and tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: The skin and its appendages are among the main organs susceptible to neoplasms in cats. Squamous cell carcinoma (SCC) is a malignant neoplasm that affects the epidermis, is locally invasive, and presents with low metastases; however, when it occurs, it spreads to the regional lymph nodes, lungs, and bone tissue. It can present in both proliferative and ulcerative forms. Its etiopathogenesis has not been fully established; however, it is associated with chronic sun exposure, papillomavirus infection, immunosuppression, and chronic skin diseases. This tumor mainly affects white-coated cats but also dark cats with hypopigmented areas, which are uncommon in dark animals and in those with good coat coverage. The objective of this study was to report a case of cutaneous SCC in a cat with black fur. Case: A 14-year-old, 4.5-kg, mixed-breed cat with black fur and a history of an ulcerated wound in the periocular region that did not heal even after previous treatment was treated with 30 mg/kg cephalexin twice a day for 15 days, 1 mg/kg prednisolone once a day for 5 days, and daily cleaning of the wound with 1% chlorhexidine twice a day for 15 days. In order to obtain a definitive diagnosis, cytological and histopathological examinations were performed. First, fine needle aspiration, an imprint, and a swab of the periocular lesion were taken. Immature or dysplastic squamous epithelium cells were observed, with keratinized polygonal angular cytoplasm, oval nuclei and coarse chromatin, a high nucleus:cytoplasm ratio, a large amount of red blood cells, and a moderate amount of segmented neutrophils, macrophages, and cocci-shaped bacteria. Fragments of malignant neoplasms invading the muscle tissue were also observed, characterized by "islands" of epithelial cells with large pleomorphic nuclei, multiple nucleoli, numerous mitotic figures, and formation of corneal pearls, leading to a diagnosis of SCC. Importantly, the animal's blood count remained unchanged. Treatment was established with the use of gabapentin [10 mg/kg - twice daily for 10 days], clindamycin [25 mg/kg - twice daily for 14 days], and piroxicam [0.3 mg/kg - every other day for 20 days]. For topical use, a cream was prepared with 5% papain, 4% hydroviton, and sunscreen (SPF 50) for use twice a day, as well as ointment based on gentamicin sulfate, sulfanilamide, sulfadiazine, urea, vitamin A palmitate, 2-3 times a day for 15 days. However, the neoplasm was already invasive, and the animal died before the treatment was completed. Discussion: Although the etiopathogenesis is not well understood, it is known that the occurrence of SCC in animals with dark fur and good coat coverage is slightly associated with chronic exposure to sunlight, which mostly affects cats with light fur or those with hypopigmented areas, as well as hair scarcity. However, in addition to ultraviolet radiation, papillomaviruses and other factors can cause SCC. The best form of diagnosis for this pathology is cytopathological examination, and if this is inconclusive, it is followed by confirmation with histopathological examination. There are several ways to treat this neoplasm, among them are surgical removals, chemotherapies, radiotherapies, photodynamic therapies, cryosurgeries, cyclooxygenase-2 and tyrosine kinase receptor inhibitors, electrochemotherapy and the use of antineoplastic agents therefore, it is important to individualize treatment according to the case and the financial status of the owner. The importance of early diagnosis is emphasized so that the tumor does not become invasive and metastasize over time, thus increasing the chances of a cure. [ABSTRACT FROM AUTHOR]

Background: Human papillomaviruses (HPVs) induce a subset of head and neck squamous cell carcinomas (HNSCC) and anogenital cancers, particularly cervical cancer (CC). The major viral proteins that contribute to tumorigenesis are the E6 and E7 oncoproteins, whose expression is usually enhanced after the integration of viral DNA into the host genome. Recently, an alternative tumorigenesis pathway has been suggested in approximately half of HNSCC and CC cases associated with HPV infection. This pathway is characterized by extrachromosomal HPV persistence and increased expression of the viral E2, E4, and E5 genes. The E6, E7, E5, and E2 proteins have been shown to modify the expression of numerous cellular immune-related genes. The antitumor immune response is a critical factor in the prognosis of HPV-driven cancers, and its characterization may contribute to the prediction and personalization of the increasingly used cancer immunotherapy. Methods: We analyzed the immune characteristics of HPV-dependent tumors and their association with carcinogenesis types. Transcriptomic HNSCC and CC datasets from The Cancer Genome Atlas were used for this analysis. Results: Clustering with immune-related genes resulted in two clusters of HPV16-positive squamous cell carcinomas in both tumor types: cluster 1 had higher activation of immune responses, including stimulation of the antigen processing and presentation pathway, which was associated with higher immune cell infiltration and better overall survival, and cluster 2 was characterized by keratinization. In CC, the distribution of tumor samples into clusters 1 and 2 did not depend on the level of E2/E5 expression, but in HNSCC, most E2/E5-high tumors were localized in cluster 1 and E2/E5-low tumors in cluster 2. Further analysis did not reveal any association between the E2/E5 levels and the expression of immune-related genes. Conclusions: Our results suggest that while the detection of immune responses associated with preserved expression of genes encoding components of antigen processing and presentation machinery in HPV-driven tumors may be markers of better prognosis and an important factor in therapy selection, the type of carcinogenesis does not seem to play a decisive role in the induction of antitumor immunity. [ABSTRACT FROM AUTHOR]

The virome of the skin, defined as all viruses detected in the skin, represents a significant part of the microbiota. A much more recent discovery than the bacterial flora, the existence of the cutaneous virome has been revealed by recent metagenomic studies. The normal human skin virome is dominated by bacteriophages, Papillomaviridae , whose genomic diversity has proved extraordinary, and Polyomaviridae. Many yet unknown viral genomes within this virome await identification. The composition of the virome of the skin has been shown to be strictly individual and relatively stable over time, resulting from adaptation to everyone's genetics, lifestyle and mechanisms of immunological tolerance finely selected over the course of evolution. Yet little studied, the virome of the skin and all its interactions with other microbiota and the host are attracting growing interest. Indeed, constitutional or acquired alterations in the homeostasis between the commensal virome and the skin, ranging from sub-clinical viral dysbiosis to severe transformation of keratinocytes or adnexal cells, have been observed. These recent observations are stimulating the search for innovative solutions aimed at measuring or even modulating its pathological expression, with a view to personalized medicine. [ABSTRACT FROM AUTHOR]

The activity of proteins is thought to be invariably determined by their amino acid sequence or composition, but we show that a long segment of a viral protein can support infection independent of its sequence or composition. During virus entry, the papillomavirus L2 capsid protein protrudes through the endosome membrane into the cytoplasm to bind cellular factors such as retromer required for intracellular virus trafficking. Here, we show that an ~110 amino acid segment of L2 is predicted to be disordered and that large deletions in this segment abolish infectivity of HPV16 pseudoviruses by inhibiting cytoplasmic protrusion of L2, association with retromer, and proper virus trafficking. The activity of these mutants can be restored by insertion of protein segments with diverse sequences, compositions, and chemical properties, including scrambled amino acid sequences, a tandem array of a short sequence, and the intrinsically disordered region of an unrelated cellular protein. The infectivity of mutants with small in-frame deletions in this segment directly correlates with the size of the segment. These results indicate that the length of the disordered segment, not its sequence or composition, determines its activity during HPV16 pseudovirus infection. We propose that a minimal length of L2 is required for it to protrude far enough into the cytoplasm to bind cytoplasmic trafficking factors, but the sequence of this segment is largely irrelevant. Thus, protein segments can carry out complex biological functions such as Human papillomavirus pseudovirus infection in a sequence-independent manner. This finding has important implications for protein function and evolution. [ABSTRACT FROM AUTHOR]

The cottontail rabbit papillomavirus (CRPV)-associated VX2 carcinoma of the New Zealand White rabbit serves as a model system for human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCCs). The aim of this study was to evaluate the tumor-inhibiting effect of RNAi-mediated knockdown of the CRPV oncogenes, E6 and E7, using siRNA-loaded lipopolyplexes (LPPs). VX2-carcinoma-derived cells were cultured for up to 150 passages. In addition, CRPV E6 and E7 oncogenes were transiently expressed in COS-7 cells. Efficiency and safety of LPPs were evaluated in both VX2 cells and the COS-7 cell line. Both of these in vitro CRPV systems were validated and characterized by fluorescence microscopy, Western blot, and RT-qPCR. Efficient knockdown of CRPV E6 and E7 was achieved in VX2 cells and COS-7 cells pretransfected with CRPV E6 and E7 expression vectors. Knockdown of CRPV oncogenes in VX2 cells resulted in reduced viability, migration, and proliferation and led to a G0/G1 block in the cell cycle. CRPV E6 and E7 siRNA-loaded LPPs could represent promising therapeutic agents serving as a paradigm for the treatment of papillomavirus-positive cancers and could be of value for the treatment of CRPV-associated diseases in the rabbit such as papillomas and cancers of the skin. [ABSTRACT FROM AUTHOR]

Simple Summary: Vaccination against human papillomavirus (HPV) helps prevent cancer caused by this virus. Determining which viral genotypes should be included is key for developing successful vaccination strategies. Low-risk genotypes, especially HPV6 and HPV11, are associated with benign warts. However, some studies also report their presence in cancers. We reviewed the scientific literature to estimate the proportion of cancers that bear single or dual HPV6/11 infections. HPV6 and HPV11 have been reported in up to 5.5% of penile and 87.5% of laryngeal cancers; however, they have not been reported in vulvar, vaginal or oral cancers. Next, we compared the HPV6/11 genomes with HPV16, the most common high-risk HPV genotype, and observed that the similarities mainly involved the E7 gene, suggesting a limited ability to interfere with the differentiation of the host cells. These findings support the use of HPV vaccines that cover HPV6/11 not only for preventing genital warts but also for preventing specific types of cancers. High-risk human papillomavirus (HPV) is etiologically related to cervical cancer, other anogenital cancers and oropharyngeal carcinomas. Low-risk HPV, especially HPV6 and HPV11, cause genital warts and laryngeal papillomas. However, the accumulating data suggests that HPV6 and HPV11 may cause malignant lesions at non-cervical anatomic sites. This review aims to estimate the proportions of single and dual HPV6/11 infections in multiple cancers reported in the last 10 years in the Cochrane, Embasa and PubMed databases. Secondly, the genomes of HPV6/11 were compared with the most common high-risk genotype, HPV16, to determine the similarities and differences. A total of 11 articles were selected, including between one and 334 HPV+ cancer patients. The frequencies of single or dual HPV6/11 infections ranged between 0–5.5% for penile and 0–87.5% for laryngeal cancers and were null for vulvar, vaginal and oral cancers. The genomic similarities between HPV6/11 and HPV16 mainly involved the E7 gene, indicating a limited ability to block cell differentiation. The presence of single or dual HPV6/11 infections in variable proportions of penile and laryngeal cancers support the vaccination strategies that cover these genotypes, not only for preventing genital warts but also for cancer prevention. Other risk factors and co-carcinogens are likely to participate in epithelial carcinogenesis associated with low-risk HPV. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) is causally associated with 5% of cancers, including cancers of the cervix, penis, vulva, vagina, anus and oropharynx. The most carcinogenic HPV is HPV-16, which dominates the types causing cancer. There is also sufficient evidence that HPV types 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 cause cervical cancer. The L1 protein, which, when assembled into virus-like particles, induces HPV-type-specific neutralising antibodies, forms the basis of all commercial HPV vaccines. There are six licensed prophylactic HPV vaccines: three bivalent, two quadrivalent and one nonavalent vaccine. The bivalent vaccines protect from HPV types 16 and 18, which are associated with more than 70% of cervical cancers. Prophylactic vaccination targets children before sexual debut, but there are now catch-up campaigns, which have also been shown to be beneficial in reducing HPV infection and disease. HPV vaccination of adults after treatment for cervical lesions or recurrent respiratory papillomatosis has impacted recurrence. Gender-neutral vaccination will improve herd immunity and prevent infection in men and women. HPV vaccines are immunogenic in people living with HIV, but more research is needed on the long-term impact of vaccination and to determine whether further boosters are required. [ABSTRACT FROM AUTHOR]

Background and Aim: Human papillomavirus (HPV) is a widespread sexually transmitted infection (STI) with significant health implications. This study aimed to assess the reactivity of TGF, IL10, and MCP-1 with Leukotriene B4 in women diagnosed with cervical HPV infections. Additionally, we considered the histological grade and clinical stage of the patients. Materials and Methods: In this observational study, a total of 50 cervical infection samples from women diagnosed with HPV and 50 samples from healthy controls were collected between January 2nd and August 1st, 2022, from attendees of Al-Elwea Hospital for Delivery and Children. IgM and IgG antibodies against HPV antigens were detected in patient sera. Polymerase chain reaction (PCR) was employed to amplify the IL-6 gene sequences of lengths 249 and 431 base pairs. Interleukin levels were quantified using the enzyme-linked immunosorbent assay (ELISA) technique. HPV infection diagnosis was confirmed using cervical cytology (Pap smear) and HPV DNA testing before study inclusion. Results: The average age of the patients was [35.02±10.73]. The findings revealed that among papillomavirus cases, 30 (85.7%) exhibited normal levels of both IgM and IgG, while 5 cases (14.3%) showed normal IgM levels and elevated IgG levels. Additionally, 10 cases (66.7%) of papilloma demonstrated increased IgM levels and normal IgG levels, in contrast to 5 cases (33.3%) with elevated levels of both IgM and IgG. Importantly, a positive correlation was observed between IgM and IgG levels and the concentrations of TGF, MCP-1, IL-10, and LTB-4 (r=0.896**, 0.678**, 0.692**, 0.894**), (r=0.894**, 0.546**, 0.570**, 0.618**), respectively. Conclusion: The study revealed a significant positive correlation between IgM and IgG levels and the concentrations of TGF, MCP-1, IL-10, and LTB-4, indicating potential immunological interactions in HPV infection. High Ct values for both patients and controls, along with HR-HPV gene expression, suggest a proportional relationship between gene concentration and Ct value. [ABSTRACT FROM AUTHOR]

Currently, it is estimated that 15% of human neoplasms globally are caused by infectious agents, with new evidence emerging continuously. Multiple agents have been implicated in various forms of neoplasia, with viruses as the most frequent. In recent years, investigation on viral mechanisms underlying tumoral transformation in cancer development and progression are in the spotlight, both in human and veterinary oncology. Oncogenic viruses in veterinary medicine are of primary importance not only as original pathogens of pets, but also in the view of pets as models of human malignancies. Hence, this work will provide an overview of the main oncogenic viruses of companion animals, with brief notes of comparative medicine. [ABSTRACT FROM AUTHOR]

Safe and effective T cell vaccines are needed for the treatment or prevention of cancers as well as infectious agents where vaccines for neutralizing antibodies have performed poorly. Recent research highlights an important role for tissue-resident memory T cells (TRM cells) in protective immunity and the role of a subset of dendritic cells that are capable of cross-priming for the induction of TRM cells. However, efficient vaccine technologies that operate through cross-priming and induce robust CD8+ T cell responses are lacking. We developed a platform technology by genetically engineering the bovine papillomavirus L1 major capsid protein to insert a polyglutamic acid/cysteine motif in place of wild-type amino acids in the HI loop. Virus-like particles (VLPs) are formed by self-assembly in insect cells infected with a recombinant baculovirus. Polyarginine/cysteine-tagged antigens are linked to the VLP by a reversible disulfide bond. The VLP possesses self-adjuvanting properties due to the immunostimulatory activity of papillomavirus VLPs. Polyionic VLP vaccines induce robust CD8+ T cell responses in peripheral blood and tumor tissues. A prostate cancer polyionic VLP vaccine was more efficacious than other vaccines and immunotherapies for the treatment of prostate cancer in a physiologically relevant murine model and successfully treated more advanced diseases than the less efficacious technologies. The immunogenicity of polyionic VLP vaccines is dependent on particle size, reversible linkage of the antigen to the VLP, and an interferon type 1 and Toll-like receptor (TLR)3/7-dependent mechanism. [ABSTRACT FROM AUTHOR]

Simple Summary: Papillomaviruses (PV) are known to cause a variety of skin lesions in dogs, including hyperplastic papillomas (warts) and viral plaques. There are currently 24 different PV types that are fully characterized in dogs. These PV types are divided into three genera. The Chipapillomavirus genus contains the largest number of canine papillomavirus (CPV) types. The Chipapillomaviruses are recognized to cause viral plaques in dogs. These plaques are usually multiple in nature and develop most frequently on the ventrum. In the present case, a dog developed a cluster of viral plaques that was confined to the concave surface of one pinna. Papillomaviral DNA was amplified and found to be a novel CPV type. As the novel type was the 25th PV identified in domestic dogs, the PV was designated CPV25. Many of the cells within the plaque showed PV-induced cell changes, suggesting that CPV25 was the cause of the plaques. As this is the first report of CPV25, this CPV type may rarely infect dogs and may be, at most, an uncommon cause of viral plaques in dogs. While further cases are required, CPV25 may cause canine viral plaques that develop at unusual locations and have atypical histological features. A 14-year-old West Highland White terrier dog developed multiple raised plaques that were confined to the concave surface of the right pinna. Histology allowed a diagnosis of viral plaque, although the lesions contained some unusual microscopic features. A papillomaviral (PV) DNA sequence was amplified from the plaque using consensus PCR primers. The amplified sequence was used as a template to design 'outward facing' PCR primers, which allowed amplification of the complete PV DNA sequence. The sequence was 7778 bp and was predicted to code for five early genes and two late genes. The ORF L1 showed the highest (83.9%) similarity to CPV15, and phylogenetic analysis revealed the novel PV clustered with the species 3 ChiPVs. The novel PV was designated as canine papillomavirus (CPV) type 25. As CPV25 was not previously detected in a canine viral plaque, this PV type may be a rare cause of skin disease in dogs. However, as plaques that remain confined to the pinna were not previously reported in dogs, it is possible that CPV25 could be more common in plaques from this area of skin. The findings from this case expand the number of PV types that cause disease in dogs. Evidence from this case suggests that, compared to the other canine ChiPV types, infection by CPV25 results in viral plaques in atypical locations with unusual histological features. [ABSTRACT FROM AUTHOR]

Papillomaviruses (PVs), double-stranded circular DNA viruses, typically cause regressing papillomas (warts) on mucosal or keratinized epithelia of a wide spectrum of species. The viruses largely infect mammals, whereby PV infections in humans, bovines, and rabbits are extensively reported. However, studies on non-mammalian PVs, particularly avian ones, are relatively lacking and worthy of investigation. This study performed a metaanalysis post-systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines to evaluate the occurrences of avian papillomaviruses (APVs) in bird species and effective materials used for virus detection. The electronic databases Science Direct, Medline via PubMed, and Google Scholar were used to search for the journal articles. Upon article eligibility check, the QUADAS-2 was employed to assess the data. Of 1139 records, 31 were eligible for full-text review, but only 9 were significant for the final review. The results showed that APVs are highly prevalent among the Fringillidae family, with a proportion of 81%, followed by Laridae (30%) and Anatidae (13%). The pooled prevalence of APV in tissue samples was 38%, while in swab samples was 13%. Only one study reported positive APV from fecal materials (0.4%); hence, the reliability comparison between these three samples was not performed. This study concluded that APVs are most prevalent in the Fringillidae bird family, while tissues are the most suitable biological samples for APV screening and should be considered as a single sample material. From epidemiology, knowledge of APV incidences and distribution may assist in controlling papillomatosis in bird species. [ABSTRACT FROM AUTHOR]

Productive replication of human papillomaviruses (HPV) only takes place in differentiating keratinocytes. The HPV16 E8^E2 protein acts as a repressor of viral gene expression and genome replication and HPV16 E8^E2 knock-out (E8-) genomes display enhanced viral late protein expression in differentiated cells. Global transcriptome analysis of differentiated HPV16 wild-type and E8-cell lines revealed a small number of differentially expressed genes which are not related to cell cycle, DNA metabolism or keratinocyte differentiation. The analysis of selected genes suggested that deregulation requires cell differentiation and positively correlated with the expression of viral late, not early transcripts. Consistent with this, the additional knock-out of the viral E4 and E5 genes, which are known to enhance productive replication, attenuated the deregulation of these host cell genes. In summary, these data reveal that productive HPV16 replication modulates host cell transcription. • The host cell transcriptome differs between HPV16 wt and E8^E2 knock-out cell lines. • Transcriptome changes depend upon differentiation of keratinocytes. • Transcriptome changes are most likely caused by cells that have entered the productive replication cycle. [ABSTRACT FROM AUTHOR]

p16 has been used as a surrogate marker for human papillomavirus (HPV)‐related tumours. However, it remains unclear whether p16 is also a potential marker for pulmonary tumours. Herein, we report the case of an 80‐year‐old woman with a history of papillary squamous cell carcinoma of the uterine cervix, presenting with a left pulmonary tumour. A bronchoscopic biopsy revealed squamous cell carcinoma with a papillary pattern, which did not rule out pulmonary metastasis from the cervix. Immunohistochemical staining revealed that the cervical tumour was positive for p16, whereas the pulmonary tumour was negative and was effectively diagnosed as primary pulmonary carcinoma. [ABSTRACT FROM AUTHOR]

Here, using viral metagenomic method, a novel whale papillomavirus (temporarily named wPV, GenBank accession number OP856597) was discovered in a whale (Delphinapterus leucas) pharyngeal metagenomic library. The complete genome size of wPV is 7179 bp, with GC content of 54.4% and a nucleotide composition of 23.4% A, 22.3% T, 28.4% G, and 25.9% C. The viral genome has a typical papillomavirus organization pattern, and five ORFs were predicted, including two late genes encoding L1 and L2, and three early genes encoding E1, E2, and E6. Pairwise sequence comparison and phylogenetic analysis based on the L1 gene sequence indicated that wPV may be a novel species within genus Dyodeltapapillomavirus. In addition, the E2 region of wPV was predicted to have a potential recombination event. The discovery of this novel papillomavirus increases our understanding of the viral ecology of marine mammals, providing insights into possible future infectious diseases. [ABSTRACT FROM AUTHOR]

The cytoskeleton is an essential component of the cell and it is involved in multiple physiological functions, including intracellular organization and transport. It is composed of three main families of proteinaceous filaments; microtubules, actin filaments and intermediate filaments and their accessory proteins. Motor proteins, which comprise the dynein, kinesin and myosin superfamilies, are a remarkable group of accessory proteins that mainly mediate the intracellular transport of cargoes along with the cytoskeleton. Like other cellular structures and pathways, viruses can exploit the cytoskeleton to promote different steps of their life cycle through associations with motor proteins. The complexity of the cytoskeleton and the differences among viruses, however, has led to a wide diversity of interactions, which in most cases remain poorly understood. Unveiling the details of these interactions is necessary not only for a better comprehension of specific infections, but may also reveal new potential drug targets to fight dreadful diseases such as rabies disease and acquired immunodeficiency syndrome (AIDS). In this review, we describe a few examples of the mechanisms that some human viruses, that is, rabies virus, adenovirus, herpes simplex virus, human immunodeficiency virus, influenza A virus and papillomavirus, have developed to hijack dyneins, kinesins and myosins. [ABSTRACT FROM AUTHOR]

The NavDx® blood test analyzes tumor tissue modified viral (TTMV)-HPV DNA to provide a reliable means of detecting and monitoring HPV-driven cancers. The test has been clinically validated in a large number of independent studies and has been integrated into clinical practice by over 1000 healthcare providers at over 400 medical sites in the US. This Clinical Laboratory Improvement Amendments (CLIA), high complexity laboratory developed test, has also been accredited by the College of American Pathologists (CAP) and the New York State Department of Health. Here, we report a detailed analytical validation of the NavDx assay, including sample stability, specificity as measured by limits of blank (LOBs), and sensitivity illustrated via limits of detection and quantitation (LODs and LOQs). LOBs were 0–0.32 copies/μL, LODs were 0–1.10 copies/μL, and LOQs were <1.20–4.11 copies/μL, demonstrating the high sensitivity and specificity of data provided by NavDx. In-depth evaluations including accuracy and intra- and inter-assay precision studies were shown to be well within acceptable ranges. Regression analysis revealed a high degree of correlation between expected and effective concentrations, demonstrating excellent linearity (R2 = 1) across a broad range of analyte concentrations. These results demonstrate that NavDx accurately and reproducibly detects circulating TTMV-HPV DNA, which has been shown to aid in the diagnosis and surveillance of HPV-driven cancers. [ABSTRACT FROM AUTHOR]

The incidence of oropharyngeal cancers (OPC) is increasing in the world. Among OPC, those induced by human papillomaviruses have a better prognosis than non-HPV-associated OPC. The objective of this study was to highlight the relevance of HPV16 load, HPV16 DNA integration and HPV16-L1 serology on progression-free survival and overall survival of OPC patients. The PAPILLOPHAR cohort consists of 362 patients with oropharyngeal squamous cell carcinomas prospectively followed up for 5 years after treatment. Tumor biopsies and sera were collected at inclusion to investigate tumor HPV DNA/RNA characteristics and HPV16 L1 serology, respectively. Twenty-seven percent of tumor biopsies were HPV DNA- and RNA-positive and HPV16 represented 93% of HPV-positive cases. Among them, neither HPV16 viral load nor HPV16 DNA integration was associated with overall survival (OS) or progression-free survival (PFS). In contrast, high anti-HPV16 L1 antibody titers were significantly associated with a better OS and PFS. This study reveals that HPV16 load and integration are not relevant prognosis biomarkers in OPC patients. Clinical Relevance: High levels of HPV16 L1 antibodies may be useful to predict OPC patient outcome following treatment. ClinicalTrials.gov Identifier: NCT00918710, May 2017. [ABSTRACT FROM AUTHOR]

Background: Only two cases of papillomavirus infections in North American porcupines (Erethizon dorsatum) have been described thus far, and molecular investigation linked these cases to two distinct papillomavirus species. Methods: In this report, we present the clinical, histological and molecular investigation of a third case of a porcupine papillomavirus infection. Papillomatous lesions occurred on the upper and lower lip of an otherwise healthy three-year old female that was kept in captivity. Within one month, the lesions progressed into exophytic black nodules, followed by a temporary stabilization and ultimately spontaneous regression within seven months of their initial observation. PCR-based screening using specific primers for Erethizon dorsatum papillomavirus 1 and 2 revealed the presence of both these virus types, after which nanopore sequencing was used to determine the complete sequences of the two virus genomes. Results: One of the genomes shares 99.9% similarity with the only known sequence for Erethizon dorsatum papillomavirus 1, while the second represents a distinct lineage of Erethizon dorsatum papillomavirus 2, sharing only 93.3% similarity with the previously discovered strain. Conclusions: This report marks the first observation of a papillomavirus co-infection in a North American porcupine, although the individual contribution of the two virus types to the clinical presentation was not assessed. [ABSTRACT FROM AUTHOR]

Background: Bovine papillomatosis (BP) is considered the most common health problem in large cattle farms. Aim: This study attempts to confirm clinically suspected BP in cattle by polymerase chain reaction (PCR) assay, histopathology, immunohistochemistry (IHC), and genotyping analysis of local isolates. Methods: According to morphological appearance and lesion features, a cross sectional study of 54 clinically diagnosed BP cattle was assigned to this current investigation from May to August (2021) in Al-Kut district (Wasit Province, Iraq) private veterinary clinics using purposive sampling technique based on set criteria. The cattle were diagnosed clinically, and the tissues were collected and some fixed in 10% neutral buffered formalin and other stored frozen and examined by histopathological technique, IHC, and PCR assays. Results: Using PCR assay, all cattle were positive for the BPV L1 gene. According to detect the L1 gene, analysis of the phylogenetic tree showed that local BPV cattle isolates were closely related to the NCBI-BLAST BPV type-1 and type-2 of the Polish equine isolate (KF284133.1) and BPV Brazilian Bostaurus isolate (MH187961.1), respectively. Histological detection showed there were acanthosis, hyperkeratosis, epidermal thickening, severe infiltration of mononuclear cells, massive hemorrhage, dermal fibroplasias, multifocal spongiosis, moderate neovascularization, moderate to severe elongation of the retention ridge towards the dermis, parakeratosis, rings of calcification, and necrosis with nuclear pyknosis of some spinosum cells. Immunohistochemical findings of tumor necrosis factor-alpha, epidermal growth factor receptor and Fascin showed a significant variation in values of immunoreaction in the dermis and epidermis. These results ranged from negative (0) to mild positive (+1) to moderate positive (+2) reactions. Conclusion: The study provided essential molecular and genotyping data to improve our knowledge by emphasizing the crucial of IHC as an elegant diagnostic method to detect cellular alterations. [ABSTRACT FROM AUTHOR]

Canine ocular papillomas occur on the haired skin of eyelids, conjunctival epithelium, and rarely on the cornea. Using PCR typing assays with canine papillomavirus type-specific primer sets, our study confirmed that the papillomas contained canine papillomavirus type 1. The positive result from a rolling circle amplification assay indicated the CPV1 viral genome in the cells is a circular episomal form. We also successfully established the first canine corneal cell line using the conditional reprogramming method. The cells exhibited an epithelial cell morphology, grew rapidly in vitro, and could be maintained long term. For the continued growth of the canine corneal cells, feeder cells played a more important role than Rho-kinase inhibitor Y-27632. More importantly, the viral CPV1 genome was maintained in the canine corneal cells during the long-term expansion. Unlimited supplies of these cells provide as a model for the study CPV in dog cells, and a platform for drug screening for effective therapies against canine papillomavirus infection in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: A subset of human papillomaviruses (HPVs), so-called high-risk (HR)-HPVs are the causal agents of cervical, anogenital and a group of head and neck carcinomas. Additionally, HR-HPVs have been detected in extragenital tumors including in lung cancer, though their role in this heterogeneous group of malignancies remains controversial. In this review, we address the epidemiological and experimental studies regarding the role of HR-HPV in lung cancer, worldwide, and we propose potential mechanisms. The evidence suggests that HR-HPVs are involved in the development of a variable subset of lung carcinomas in both smoker and non-smoker subjects. Lung cancer is a very prevalent and heterogeneous group of malignancies, and most of them are etiologically associated with tobacco smoking. However, viral infections have been detected in lung carcinomas, with high-risk human papillomaviruses (HR-HPVs) being among them. The role of HR-HPVs in lung cancer has been considered to be controversial. This issue is due to the highly variable presence of this virus in lung carcinomas worldwide, and the low viral load frequently that is detected. In this review, we address the epidemiological and mechanistic findings regarding the role of HR-HPVs in lung cancer. Some mechanisms of HR-HPV-mediated lung carcinogenesis have been proposed, including (i) HPV works as an independent carcinogen in non-smoker subjects; (ii) HPV cooperates with carcinogenic compounds present in tobacco smoke; (iii) HPV promotes initial alterations being after cleared by the immune system through a "hit and run" mechanism. Additional research is warranted to clarify the role of HPV in lung cancer. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPV) are epitheliotropic DNA tumor viruses that are prevalent in the human population. A subset of the HPVs termed high-risk HPVs (HR-HPVs) are causative agents of anogenital cancers and head-and-neck cancers. Cancer is the result of persistent high-risk HPV infections that have not been cleared by the immune system of the host. These infections are characterized by dysregulated HPV gene expression, in particular constitutive high expression of the HPV E6 and E7 oncogenes and absence of the highly immunogenic viral L1 and L2 capsid proteins. HPVs make extensive use of alternative mRNA splicing to express its genes and are therefore highly dependent on cellular RNA-binding proteins for proper gene expression. Levels of RNA-binding proteins are altered in HPV-containing premalignant cervical lesions and in cervical cancer. Here we review our current knowledge of RNA-binding proteins that control HPV gene expression. We focus on RNA-binding proteins that control expression of the E6 and E7 oncogenes since they initiate and drive development of cancer and on the immunogenic L1 and L2 proteins as there silencing may contribute to immune evasion during carcinogenesis. Furthermore, cellular RNA-binding proteins are essential for HPV gene expression and as such may be targets for therapy to HPV infections and HPV-driven cancers. [ABSTRACT FROM AUTHOR]

Numerous large dark plaques developed over the ventrum, legs and head of a 9-year-old pug dog over a 4-year-period. Histology confirmed a diagnosis of viral pigmented plaque and a short section of a novel papillomavirus (PV) type was amplified using consensus PCR primers. Taking advantage of the circular nature of PV DNA, 'outward facing' PCR primers allowed amplification of the full sequence. As this is the 24th PV known to infect dogs, the novel PV was designated canine papillomavirus (CPV) type 24. The CPV24 genome contained putative coding regions for 5 early proteins and 2 late ones. The CPV24 open reading frame L1 showed the highest (78.2%) similarity to CPV4 and phylogenetic analysis showed that CPV24 clustered with CPV4 and CPV16 suggesting CPV24 is the third species 2 Chipapillomavirus type identified in dogs. This is the third report of extensive pigmented plaques covering a high proportion of the skin. Both previous cases were caused CPV4 and, considering the high genetic similarity between CPV4 and CP24, infection by these CPV types may predispose to more severe clinical disease. In addition, as plaques caused by CPV16 appear more likely to progress to neoplasia, the detection of a species 2 Chipapillomavirus within a pigmented plaque may indicate the potential for more severe disease. [ABSTRACT FROM AUTHOR]

Sarcoid is one of the most common skin tumours, which is diagnosed in various breeds of horses at any age regardless of the animal’s sex. Such fibroblastic neoplasm manifests itself in several clinical ways with its specific morphological features. As a rule, it metastasizes rarely but can be locally invasive. The disease’setiology is multifactorial and includes the confirmed role of the bovine papillomavirus and genetic and environmental factors. The article introduces the results of a retrospective study of horses of the Ukrainian riding breed with a fibroblastic sarcoid type, which was localized mainly in the area of the external thoracic vein. Neoplasms were represented by two types. The first one included broad base neoplasms without a pronounced pedicle but with signs of hyperkeratosis. Massive rounded dense formations with an ulcerated surface refer to the second type. To verify the studied types of sarcoid, wide surgical excision of the lesion’svisible parts was performed, followed by the selection of fragments for the pathohistological diagnosis. Also, additional staining methods were used to detect the connective and muscle tissue (Van Gieson’s staining) and elastic fibers (Weigert’sresorcin-fuchsin staining). Microscopically, the neoplasm without a visible pedicle showed signs of hyperkeratosis and acanthosis in the peritumoral epidermal layer. Epidermis desquamation with a significant amount of oxyphilic detritus, diapedesis hemorrhages, and dilated vessels was also detected in some areas.Chaotic placement of fibroblasts and fibrocytes was noted, to a greater extent, subdermally. Anisocytosis and anisokaryosis were expressed moderately. Sarcoids, macroscopically presented in the form of massive dense formations with an ulcerated surface, were histologically characterized by the replacement of the epidermis with cellular elements, subdermal hemorrhages, and the characteristic perpendicular orientation of coarse collagen fibers towards the basement membrane. Closely spaced spindle-shaped cells with fibers forming moiré structures were visualized in the deep dermis layers. Nuclei were hyperchromic and elongated in shape, no atypical mitoses were noted. Pathohistological examination during the identification of a sarcoid type for diagnostic purposes can cause rapid growth and formation of an ulcer. The final diagnosis regarding equine sarcoid can be made based on a combination of clinical signs, histopathological examination, and molecular genetic testing with the isolation of BPV DNA. [ABSTRACT FROM AUTHOR]

Proteins of the bromodomain and exterminal domain (BET) family mediate critical host functions such as cell proliferation, transcriptional regulation, and the innate immune response, which makes them preferred targets for viruses. These multidomain proteins are best known as transcriptional effectors able to read acetylated histone and non-histone proteins through their tandem bromodomains. They also contain other short motif-binding domains such as the extraterminal domain, which recognizes transcriptional regulatory proteins. Here, we describe how different viruses have evolved to hijack or disrupt host BET protein function through direct interactions with BET family members to support their own propagation. The network of virus-BET interactions emerges as highly intricate, which may complicate the use of small-molecule BET inhibitors–currently in clinical development for the treatment of cancer and cardiovascular diseases–to treat viral infections. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) cause a substantial amount of human disease from benign disease such as warts to malignant cancers including cervical carcinoma, head and neck cancer, and non-melanoma skin cancer. Our ability to model HPV-induced malignant disease has been impeded by species specific barriers and pre-clinical animal models have been challenging to develop. The recent discovery of a murine papillomavirus, MmuPV1, that infects laboratory mice and causes the same range of malignancies caused by HPVs provides the papillomavirus field the opportunity to test mechanistic hypotheses in a genetically manipulatable laboratory animal species in the context of natural infections. The E6 and E7 proteins encoded by high-risk HPVs, which are the HPV genotypes associated with human cancers, are multifunctional proteins that contribute to HPV-induced cancers in multiple ways. In this review, we describe the known activities of the MmuPV1-encoded E6 and E7 proteins and how those activities relate to the activities of HPV E6 and E7 oncoproteins encoded by mucosal and cutaneous high-risk HPV genotypes. [ABSTRACT FROM AUTHOR]

Approximately 5% of all human cancers are attributable to human papillomavirus (HPV) infections. HPV-associated diseases and cancers remain a substantial public health and economic burden worldwide despite the availability of prophylactic HPV vaccines. Current diagnosis and treatments for HPV-associated diseases and cancers are predominantly based on cell/tissue morphological examination and/or testing for the presence of high-risk HPV types. There is a lack of robust targets/markers to improve the accuracy of diagnosis and treatments. Several naturally occurring animal papillomavirus models have been established as surrogates to study HPV pathogenesis. Among them, the Cottontail rabbit papillomavirus (CRPV) model has become known as the gold standard. This model has played a pivotal role in the successful development of vaccines now available to prevent HPV infections. Over the past eighty years, the CRPV model has been widely applied to study HPV carcinogenesis. Taking advantage of a large panel of functional mutant CRPV genomes with distinct, reproducible, and predictable phenotypes, we have gained a deeper understanding of viral–host interaction during tumor progression. In recent years, the application of genome-wide RNA-seq analysis to the CRPV model has allowed us to learn and validate changes that parallel those reported in HPV-associated cancers. In addition, we have established a selection of gene-modified rabbit lines to facilitate mechanistic studies and the development of novel therapeutic strategies. In the current review, we summarize some significant findings that have advanced our understanding of HPV pathogenesis and highlight the implication of the development of novel gene-modified rabbits to future mechanistic studies. [ABSTRACT FROM AUTHOR]

Background/Aim. Human papillomaviruses (HPV) are the most common cause of sexually transmitted infections. Most HPV infections are transient and asymptomatic. Routine vaccination against HPV is the best prophylaxis against HPV infection. The aim of the study was to determine knowledge and risk factors about HPV infection and the attitudes towards vaccination against HPV among nursing students. Methods. This cross-sectional study was conducted on a random sample of 175 nursing students.The students were divided into categories according to their year of studying. Statistical data analysis was done using the t-test and Mann-Whitney U test. Results. Most (93.1%) respondents knew that HPV infection might cause cervical cancer and that it was a sexually transmitted infection (80.0%). Only 31.4% were aware that HPV might cause head and neck cancer, and 22.9% were aware that smoking was a risk factor for HPV infection. Male respondents (p < 0.05) and third-year respondents (p < 0.05) were significantly aware that men could also be infected with HPV. Third-year respondents were significantly aware that early sexual intercourse increased the risk of HPV infection (p < 0.05) and that HPV infection could be asymptomatic (p < 0.05). Respondents under 26 years of age (p < 0.05) and first-year respondents (p < 0.05) were significantly aware that men could as well be vaccinated against HPV. Conclusion. The present study found that the respondents emphasized the importance of health education by nurses and vaccination against HPV. Due to the low vaccination rate of the population, preventive measures are needed to increase public awareness about vaccination against HPV, for which nurses are also responsible. [ABSTRACT FROM AUTHOR]

Human papillomavirus 16 (HPV16) E2 is a DNA-binding protein that regulates transcription, replication and potentially, segregation of the HPV16 genome during the viral life cycle. In the segregation model, E2 simultaneously binds to viral and host chromatin, acting as a bridge to ensure that viral genomes reside in daughter nuclei following cell division. The host chromatin receptor for E2 mediating this function is unknown. Recently, we demonstrated that CK2 phosphorylation of E2 on serine 23 (S23) is required for interaction with TopBP1, and that this interaction promotes E2 and TopBP1 recruitment to mitotic chromatin. Here, we demonstrate that in U2OS cells expressing wild-type E2 and a non-TopBP1-binding mutant (S23A, serine 23 mutated to alanine), interaction with TopBP1 is essential for E2 recruitment of plasmids to mitotic chromatin. Using novel quantitative segregation assays, we demonstrate that interaction with TopBP1 is required for E2 plasmid segregation function in U2OS and N/Tert-1 cells. Small interfering RNA (siRNA) knockdown of TopBP1 or CK2 enzyme components disrupts E2 segregation/retention function. The interaction of E2 with TopBP1 promotes increased levels of E2 protein during mitosis in U2OS and N/Tert-1 cells, as well as in human foreskin keratinocytes (HFK) immortalized by the HPV16 genome. Overall, our results demonstrate that E2 has plasmid segregation activity, and that the E2-TopBP1 interaction is essential for this E2 function. [ABSTRACT FROM AUTHOR]

We have established a mouse papillomavirus (MmuPV1) model that induces both cutaneous and mucosal infections and cancers. In the current study, we use this model to test our hypothesis that passive immunization using a single neutralizing monoclonal antibody can protect both cutaneous and mucosal sites at different time points after viral inoculation. We conducted a series of experiments involving the administration of either a neutralizing monoclonal antibody, MPV.A4, or control monoclonal antibodies to both outbred and inbred athymic mice. Three clinically relevant mucosal sites (lower genital tract for females and anus and tongue for both males and females) and two cutaneous sites (muzzle and tail) were tested. At the termination of the experiments, all tested tissues were harvested for virological analyses. Significantly lower levels of viral signals were detected in the MPV.A4-treated female mice up to 6 h post-viral inoculation compared to those in the isotype control. Interestingly, males displayed partial protection when they received MPV.A4 at the time of viral inoculation, even though they were completely protected when receiving MPV.A4 at 24 h before viral inoculation. We detected MPV.A4 in the blood starting at 1 h and up to 8 weeks postadministration in some mice. Parallel to these in vivo studies, we conducted in vitro neutralization using a mouse keratinocyte cell line and observed complete neutralization up to 8 h post-viral inoculation. Thus, passive immunization with a monoclonal neutralizing antibody can protect against papillomavirus infection at both cutaneous and mucosal sites and is time dependent. [ABSTRACT FROM AUTHOR]

The artemisinin family of compounds is cytopathic in certain cancer cell lines that are positive for human papillomaviruses (HPV) and can potentially drive the regression of dysplastic lesions. We evaluated the efficacy of topical dihydroartemisinin (DHA) on cervical dysplasia and anal dysplasia in two papillomavirus mouse models: K14E6/E7 transgenic mice, which express HPV16 oncogenes; and immunodeficient NOD/SCID gamma (NSG) mice infected with Mus musculus papillomavirus (MmuPV1). Mice started treatment with DHA at 25 weeks of age (K14E6/E7) or 20 weeks post infection (MmuPV1-infected), when the majority of mice are known to have papillomavirus-induced low- to high-grade dysplasia. Mice were treated with or without topical DHA at the cervix or anus and with or without topical treatment with the chemical carcinogen 7,12 dimethylbenz(a)anthracene (DMBA) at the anus of in transgenic mice to induce neoplastic progression. Mice were monitored for overt tumor growth, and tissue was harvested after 20 weeks of treatment and scored for severity of histological disease. For MmuPV1-infected mice, anogenital lavages were taken to monitor for viral clearance. Tissues were also evaluated for viral gene expression at the RNA and/or protein levels. Treatment with topical DHA did not reduce dysplasia in the anogenital tract in either papillomavirus-induced mouse model and did not prevent progression to anal cancer in the DMBA-treated K14E6/E7 mice. [ABSTRACT FROM AUTHOR]

FMS-related tyrosine kinase 3 ligand (FLT3L), encoded by FLT3LG , is a hematopoietic factor essential for the development of natural killer (NK) cells, B cells, and dendritic cells (DCs) in mice. We describe three humans homozygous for a loss-of-function FLT3LG variant with a history of various recurrent infections, including severe cutaneous warts. The patients' bone marrow (BM) was hypoplastic, with low levels of hematopoietic progenitors, particularly myeloid and B cell precursors. Counts of B cells, monocytes, and DCs were low in the patients' blood, whereas the other blood subsets, including NK cells, were affected only moderately, if at all. The patients had normal counts of Langerhans cells (LCs) and dermal macrophages in the skin but lacked dermal DCs. Thus, FLT3L is required for B cell and DC development in mice and humans. However, unlike its murine counterpart, human FLT3L is required for the development of monocytes but not NK cells. [Display omitted] • Human FLT3L deficiency underlies bone-marrow failure and infectious diseases • Human and mouse FLT3L deficiencies impair dendritic and B cell development • FLT3L deficiency impairs monocyte development in humans but not mice • FLT3L deficiency impairs NK cell development in mice but not in humans Adult humans with inherited, complete FLT3L deficiency enable valuable insights into the role of the hematopoietic growth factor FLT3L in human hematopoiesis, revealing that FLT3L deficiencies impair monocyte, dendritic, and B cell development but not NK cell development. This study reveals key differences in the role of FLT3L in humans versus mice. [ABSTRACT FROM AUTHOR]

In this study, the impedimetric biosensor of human papillomavirus DNA (HPV DNA) in label-free approach based on indium oxide nanowires (In2O3 NWs) was fabricated. The fabrication of In2O3 NWs was successfully conducted using the thermal evaporation method and catalyst-free approach. The grown NWs had a diameter of about 70–90 nm and a length of several microns. The fabricated electrode was able to show high selectivity by changing the relative charge transfer resistance of 80, 60 and 50% for complementary, mismatch and non-complementary sequences, respectively. The electrode biosensor was stable for up to 6 weeks under the effect of electric field and showed 93% of its initial response sensitivity and detected DNA hybridization at very low concentrations in a linear response range from 0.1 pM to 0.1 μM. The In2O3 NWs showed a detection of limit (LOD) 20 fM. The behavior of negatively charged DNA oligonucleotides in a nanostructured array under the influence of electric field brought about NWs in the preferred direction with an excellent analytical response. Compared to current biosensors, the designed and fabricated biosensor, in a suitable sensing mechanism, was able to optimize response sensitivity and stability and also could improve the reproducibility conditions. [ABSTRACT FROM AUTHOR]

Background: The spread of cervical squamous cell carcinoma to the inner surface of the uterus with replacement of the endometrium is rare. Continuity of the lesion must be demonstrated to confirm superficial spread and rule out concomitant endometrial cancer.Case Presentation: We present the case of a 66-year-old white woman with superficial spreading squamous cell carcinoma of the cervix that involved the endometrium. Her relevant past history included conization of the cervix to treat cervical intraepithelial neoplasia III with positive margins. She subsequently had three negative cervical vaginal cytology results, each with a positive high-risk human papillomavirus test. Transvaginal ultrasound showed occupation of the entire uterine cavity by dense material consistent with pyometra in addition to myometrial thinning due to tension and cervical dilation. The patient presented with greenish vaginal discharge of 3 months' duration. The cervix was not visible during speculum examination. Access for endometrial sampling was not possible, raising suspicion of post-conization cervical stenosis. The patient was treated with laparoscopic hysterectomy with double adnexectomy. Histologic examination showed superficial squamous cell carcinoma invading the cervix to a depth of 2.8 mm; superficial spreading squamous cell carcinoma in situ was also observed in the lower uterine segment and endometrium. The patient was free of symptoms 12 months after surgery.Conclusions: Squamous cell carcinoma of the cervix with superficial spread to the endometrium is not included in the 2020 (fifth edition) World Health Organization Classification of Female Genital Tract Tumors or the 2018 International Federation of Gynecology and Obstetrics cervical cancer staging system. More clinical cases are needed to identify other prognostic factors and inform clinical practice guidelines on the management of this disease. [ABSTRACT FROM AUTHOR]

Purpose: Human papillomavirus (HPV) genotype and age distribution of HPV infection were crucial for the national vaccination and screening program planning. However, there was a limited study providing these data in the normal cervix population. This study aimed to explore the HPV genotypes profile of women with clinically normal cervix based on Visual Inspection of Acetic Acid (VIA) test. Materials and Methods: A 7-year cross-sectional study was conducted from 2012 to 2018 in private and public health care centers in Jakarta. Subjects were recruited consecutively. Data were collected by anamnesis, VIA, and HPV DNA test using the polymerase chain reaction (PCR; SPF10-DEIA-LiPA25) method. HPV genotyping procedures include DNA extraction, PCR (SPF10-DEIA-LiPA25) using the HPV XpressMatrix kit (PT KalGen DNA, East Jakarta, Indonesia), and hybridization. The IBM SPSS ver. 20.0 (IBM Corp., Armonk, NY, USA) were used to analyze the data. Results: A total of 1,397 subjects were collected. Positive HPV-DNA tests were found in 52 subjects (3.7%); 67% were single and 33% were multiple HPV infections. HPV 52 was the most frequently detected HPV genotype, followed by HPV 39, 16, 18 74, 44, 31, 54, and 66, respectively. The highest HPV infections in this population were in the 31-40 and 41-50 years old group. Conclusion: This study suggested beneficial screening for women aged 31-50 years old. Instead of "original" nonavalent (HPV 16, 18, 6, 11, 31, 33, 45, 52, 58), the different "nonavalent" formula for HPV vaccines protecting against HPV 16, 18, 6, 11, 31, 39, 44, 52, 74 might be useful for Indonesian population. However, further multicenter studies with a huge sample size are still needed. [ABSTRACT FROM AUTHOR]

Laryngeal infection with low-risk human papillomaviruses can cause recurrent respiratory papillomatosis (RRP), a disease with severe effects on vocal fold epithelium resulting in impaired voice function and communication. RRP research has been stymied by limited preclinical models. We recently reported a murine model of laryngeal MmuPV1 infection and disease in immunodeficient mice. In the current study, we compare quantitative and qualitative measures of epithelial proliferation, apoptosis, differentiation, and barrier between mice with MmuPV1-induced disease of the larynx and surrounding tissues and equal numbers of uninfected controls. Findings supported our hypothesis that laryngeal MmuPV1 infection recapitulates many features of RRP. Like RRP, MmuPV1 increased proliferation in infected vocal fold epithelium, expanded the basal compartment of cells, decreased differentiated cells, and altered cell–cell junctions and basement membrane. Effects of MmuPV1 on apoptosis were equivocal, as with RRP. Barrier markers resembled human neoplastic disease in severe MmuPV1-induced disease. We conclude that MmuPV1 infection of the mouse larynx provides a useful, if imperfect, preclinical model for RRP that will facilitate further study and treatment development for this intractable and devastating disease. [ABSTRACT FROM AUTHOR]

Recurrent respiratory papillomatosis (RRP), caused by laryngeal infection with low-risk human papillomaviruses, has devastating effects on vocal communication and quality of life. Factors in RRP onset, other than viral presence in the airway, are poorly understood. RRP research has been stalled by limited preclinical models. The only known papillomavirus able to infect laboratory mice, Mus musculus papillomavirus (MmuPV1), induces disease in a variety of tissues. We hypothesized that MmuPV1 could infect the larynx as a foundation for a preclinical model of RRP. We further hypothesized that epithelial injury would enhance the ability of MmuPV1 to cause laryngeal disease, because injury is a potential factor in RRP and promotes MmuPV1 infection in other tissues. In this report, we infected larynges of NOD scid gamma mice with MmuPV1 with and without vocal fold abrasion and measured infection and disease pathogenesis over 12 weeks. Laryngeal disease incidence and severity increased earlier in mice that underwent injury in addition to infection. However, laryngeal disease emerged in all infected mice by week 12, with or without injury. Secondary laryngeal infections and disease arose in nude mice after MmuPV1 skin infections, confirming that experimentally induced injury is dispensable for laryngeal MmuPV1 infection and disease in immunocompromised mice. Unlike RRP, lesions were relatively flat dysplasias and they could progress to cancer. Similar to RRP, MmuPV1 transcript was detected in all laryngeal disease and in clinically normal larynges. MmuPV1 capsid protein was largely absent from the larynx, but productive infection arose in a case of squamous metaplasia at the level of the cricoid cartilage. Similar to RRP, disease spread beyond the larynx to the trachea and bronchi. This first report of laryngeal MmuPV1 infection provides a foundation for a preclinical model of RRP. [ABSTRACT FROM AUTHOR]

Papillomaviruses (PV) replicate in undifferentiated keratinocytes at low levels and to high levels in differentiated cells. The restricted replication in undifferentiated cells is mainly due to the expression of the conserved viral E8^E2 repressor protein, a fusion protein consisting of E8 and the hinge, DNA-binding, and dimerization domain of E2. E8^E2 binds to viral genomes and represses viral transcription and genome replication by recruiting cellular NCoR/SMRT-HDAC3 corepressor complexes. Tissue culture experiments have revealed that E8^E2 modulates long-term maintenance of extrachromosomal genomes, productive replication, and immortalization properties in a virus type-dependent manner. Furthermore, in vivo experiments have indicated that Mus musculus PV1 E8^E2 is required for tumor formation in immune-deficient mice. In summary, E8^E2 is a crucial inhibitor whose levels might determine the outcome of PV infections. [ABSTRACT FROM AUTHOR]

Keywords: horse; papillomavirus EN horse papillomavirus 236 240 5 04/12/22 20220501 NES 220501 Introduction The case report that this clinical commentary accompanies (Vichi I et al i . 2022) describes the diagnosis and treatment of a 2-year-old horse with cutaneous papillomatosis lesions, attributed to I Equus caballus i papillomavirus 2 (EcPV2) infection, and concurrent cutaneous habronemiasis. Some equine PV infections involve persistent productive infections and lesions, for example, chronic genital papillomas associated with EcPV2 infection (Knight I et al i . 2011). Equids have traditionally been considered dead end hosts of BPV because infective virions have not been isolated from equine sarcoids as they can be from bovine papillomas (Hainisch I et al i . 2017). [Extracted from the article]

Intracellular trafficking of human papillomavirus (HPV) during virus entry requires γ-secretase, a cellular protease consisting of a complex of four cellular transmembrane (TM) proteins. γ-secretase typically cleaves substrate proteins but it plays a non-canonical role during HPV entry. γ-secretase binds to the HPV minor capsid protein L2 and facilitates its insertion into the endosomal membrane. After insertion, L2 protrudes into the cytoplasm, which allows HPV to bind other cellular factors required for proper virus trafficking into the retrograde transport pathway. Here, we further characterize the interaction between γ-secretase and HPV L2. We show that γ-secretase is required for cytoplasmic protrusion of L2 and that L2 associates strongly with the PS1 catalytic subunit of γ-secretase and stabilizes the γ-secretase complex. Mutational studies revealed that a putative TM domain in HPV16 L2 cannot be replaced by a foreign TM domain, that infectivity of HPV TM mutants is tightly correlated with γ-secretase binding and stabilization, and that the L2 TM domain is required for protrusion of the L2 protein into the cytoplasm. These results provide new insight into the interaction between γ-secretase and L2 and highlight the importance of the native HPV L2 TM domain for proper virus trafficking during entry. [ABSTRACT FROM AUTHOR]

Human papillomaviruses (HPVs) are nonenveloped double-stranded DNA viruses that utilize heparan sulfate proteoglycans (HSPGs) as initial attachment factors prior to cell entry and infection. While extensively characterized, the selective interaction between HPV and HSPGs is generally studied using standard in vitro conditions, which fail to account for the effects that media additives, such as fetal bovine serum (FBS), can have on viral binding. As environmental conditions and growth factors associated with wound healing are thought to play a role in natural HPV infection, we sought to investigate the effects that serum or platelet extracts could have on the binding and infectivity of HPV. Here, we demonstrate that high concentrations of FBS and human serum greatly inhibit HPV16 binding, and that for FBS, this effect results from the obstruction of cell surface HSPGs by serum-derived heparin-binding proteins (HBPs). Surprisingly, we found that under these conditions, HPV particles utilize 6O-sulfated chondroitin sulfate proteoglycans (CSPGs) as initial binding receptors prior to infection. These findings were corroborated by small interfering RNA (siRNA)-mediated knockdown experiments, as well as through a cancer cell line screen, where we identified a strong association between viral binding in high serum and the expression of chondroitin sulfate biosynthesis genes. Furthermore, HPV binding in the presence of human platelet lysate also demonstrated an increased dependance on CSPGs, suggesting a possible role for these receptor proteoglycans in active wound healing environments. Overall, this work highlights the significant influence that serum/platelet factors can have on virus binding and identifies CSPGs as alternative cell attachment receptors for HPV. IMPORTANCE Heparan sulfate proteoglycans (HSPGs) have previously been identified as primary attachment factors for the initial binding of human papillomaviruses (HPVs) prior to infection. Here, we demonstrate that in vitro, HPV binding to HSPGs is strongly dependent on the surrounding experimental conditions, including the concentration of fetal bovine serum (FBS). We found that high concentrations of FBS can block HSPG-binding sites and cause a dependence on 6O-sulfated chondroitin sulfate proteoglycans (CSPGs) as alternative initial viral receptors. Further, we demonstrate that use of a human-derived alternative to FBS, human platelet lysate, also occludes HSPG-dependent binding, causing a shift toward CSPGs for viral attachment. As HPV infection of basal epithelial cells is thought to occur at sites of microtrauma with exposure to high serum levels and platelet factors, these unexpected findings highlight a possible role for CSPGs as important cellular receptors for the binding and infectivity of HPV in vivo. [ABSTRACT FROM AUTHOR]

Purpose: The precise etiopathogenesis of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC), and reasons for predilection for crypt epithelium, remain uncertain. The purpose of this study is to investigate the interaction between HPV and specific cytokeratins 7 (CK7) and 19 (CK19) in crypt epithelium. Methods: This is a retrospective cohort study of patients presenting between 1999 and 2015 at a tertiary referral center. CK7 and CK19 positivity and H Scores were determined by immunohistochemistry. Disease-specific and overall survival rates were analyzed. Results: There were 253 patients presenting with OPSCC (134), squamous cell carcinoma (SCC) of unknown primary site (22), and oral tongue SCC (97). Primary tumor CK7 and CK19 positivity and H Scores were significantly higher in HPV-positive OPSCC than HPV-negative OPSCC and oral tongue SCC. Higher CK19 Scores, but not CK7 Scores, were also seen in regional metastases from HPV-positive OPSCC than other sites. No impact on disease-specific or overall survival was identified on multivariate analysis. Conclusion: The increased expression of CK7 and CK19 in HPV-positive OPSCC compared to HPV-negative disease supports the theory for a role for these cytokeratins in the etiopathogenesis of HPV-related OPSCC. [ABSTRACT FROM AUTHOR]