scholarly journals Vesicular trafficking permits evasion of cGAS/STING surveillance during initial human papillomavirus infection

2020 ◽  
Vol 16 (11) ◽  
pp. e1009028
Author(s):  
Brittany L. Uhlorn ◽  
Robert Jackson ◽  
Shuaizhi Li ◽  
Shauna M. Bratton ◽  
Koenraad Van Doorslaer ◽  
...  
Keyword(s):  
Viral Entry ◽  
Hpv Infection ◽  
Vesicular Trafficking ◽  
Cationic Lipids ◽  
Human Papillomaviruses ◽  
Cell Nuclei ◽  
Dna Viruses ◽  
Papillomavirus Infection ◽  
Defective Mutant ◽  
Microbial Infections

Oncogenic human papillomaviruses (HPVs) replicate in differentiating epithelium, causing 5% of cancers worldwide. Like most other DNA viruses, HPV infection initiates after trafficking viral genome (vDNA) to host cell nuclei. Cells possess innate surveillance pathways to detect microbial components or physiological stresses often associated with microbial infections. One of these pathways, cGAS/STING, induces IRF3-dependent antiviral interferon (IFN) responses upon detection of cytosolic DNA. Virion-associated vDNA can activate cGAS/STING during initial viral entry and uncoating/trafficking, and thus cGAS/STING is an obstacle to many DNA viruses. HPV has a unique vesicular trafficking pathway compared to many other DNA viruses. As the capsid uncoats within acidic endosomal compartments, minor capsid protein L2 protrudes across vesicular membranes to facilitate transport of vDNA to the Golgi. L2/vDNA resides within the Golgi lumen until G2/M, whereupon vesicular L2/vDNA traffics along spindle microtubules, tethering to chromosomes to access daughter cell nuclei. L2/vDNA-containing vesicles likely remain intact until G1, following nuclear envelope reformation. We hypothesize that this unique vesicular trafficking protects HPV from cGAS/STING surveillance. Here, we investigate cGAS/STING responses to HPV infection. DNA transfection resulted in acute cGAS/STING activation and downstream IFN responses. In contrast, HPV infection elicited minimal cGAS/STING and IFN responses. To determine the role of vesicular trafficking in cGAS/STING evasion, we forced premature viral penetration of vesicular membranes with membrane-perturbing cationic lipids. Such treatment renders a non-infectious trafficking-defective mutant HPV infectious, yet susceptible to cGAS/STING detection. Overall, HPV evades cGAS/STING by its unique subcellular trafficking, a property that may contribute to establishment of infection.

scholarly journals Vesicular Trafficking Permits Evasion of cGAS/STING Surveillance During Initial Human Papillomavirus Infection

2020 ◽  
Author(s):  
Brittany L. Uhlorn ◽  
Robert Jackson ◽  
Shauna M. Bratton ◽  
Shuaizhi Li ◽  
Koenraad Van Doorslaer ◽  
...  
Keyword(s):  
Viral Entry ◽  
Viral Infections ◽  
Hpv Infection ◽  
Vesicular Trafficking ◽  
Cationic Lipids ◽  
Human Papillomaviruses ◽  
Cell Nuclei ◽  
Dna Viruses ◽  
Microbial Infections ◽  
Sting Pathway

AbstractOncogenic human papillomaviruses (HPVs) replicate in differentiating epithelium, causing 5% of cancers worldwide. Like most other DNA viruses, HPV infection initiates after trafficking viral genome (vDNA) to host cell nuclei. Cells possess innate surveillance pathways to detect microbial components or physiological stresses often associated with microbial infections. One of these pathways, cGAS/STING, induces IRF3-dependent antiviral interferon (IFN) responses upon detection of cytosolic DNA. Virion-associated vDNA can activate cGAS/STING during initial viral entry and uncoating/trafficking, and thus cGAS/STING is an obstacle to many DNA viruses. HPV has a unique vesicular trafficking pathway compared to many other DNA viruses. As the capsid uncoats within acidic endosomal compartments, minor capsid protein L2 protrudes across vesicular membranes to facilitate transport of vDNA to the Golgi. L2/vDNA resides within the Golgi lumen until G2/M, whereupon vesicular L2/vDNA traffics along spindle microtubules, tethering to chromosomes to access daughter cell nuclei. L2/vDNA-containing vesicles likely remain intact until G1, following nuclear envelope reformation. We hypothesize that this unique vesicular trafficking protects HPV from cGAS/STING surveillance. Here, we investigate cGAS/STING responses to HPV infection. DNA transfection resulted in acute cGAS/STING activation and downstream IFN responses. In contrast, HPV infection elicited minimal cGAS/STING and IFN responses. To determine the role of vesicular trafficking in cGAS/STING evasion, we forced premature viral penetration of vesicular membranes with membrane-perturbing cationic lipids. Such treatment renders a non-infectious trafficking-defective mutant HPV infectious, yet susceptible to cGAS/STING detection. Overall, HPV evades cGAS/STING by its unique subcellular trafficking, a property that may contribute to establishment of infection.ImportancePersistent infection is the main risk factor for all HPV-associated cancers. However, cellular innate immune pathways exist to detect and limit viral infections. The cGAS/STING pathway senses cytosolic DNA to initiate antiviral IFN responses. Such responses would likely be detrimental towards the establishment of persistent HPV infections. We therefore hypothesize that HPV evades cGAS/STING detection via its unique vesicular trafficking mechanism. Here, we show that indeed HPV is a stealthy virus, capable of infecting keratinocytes with minimal activation of the cGAS/STING pathway. Such evasion is dependent on HPV’s vesicular trafficking, as perturbation of vesicular integrity during infection results in sensing of virions.

scholarly journals Papillomavirus can be transmitted through the blood and produce infections in blood recipients: Evidence from two animal models

2019 ◽  
Author(s):  
Nancy M. Cladel ◽  
Pengfei Jiang ◽  
Jingwei J. Li ◽  
Xuwen Peng ◽  
Timothy K. Cooper ◽  
...  
Keyword(s):  
Animal Models ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Viral Dna ◽  
Internal Organs ◽  
Sexually Transmitted ◽  
Potential Source ◽  
Papillomavirus Infection ◽  
Blood Banks ◽  
Gain Access

AbstractHuman papillomavirus (HPV) infections are commonly thought to be strictly sexually transmitted. However, studies have demonstrated the presence of HPV in cancers of many non-sexual internal organs, raising the question as to how the viruses gain access to these sites. A possible connection between blood transfusion and HPV-associated disease has not received much attention. We show, in two animal models, that blood infected with papillomavirus yields infections at permissive sites. Furthermore, we demonstrate that blood from actively infected mice can transmit the infection to naïve animals. Finally, we report papillomavirus infections in the stomach tissues of animals infected via the blood. Stomach tissues are not known to be permissive for papillomavirus infection, although the literature suggests that HPVs may be associated with a subset of gastric cancers. These results indicate that the human blood supply, which is not screened for papillomaviruses, could be a potential source of HPV infection and subsequent cancers.SUMMARYHuman papillomaviruses cause 5% of human cancers. Currently, blood banks do not screen for these viruses. We demonstrate that blood transfused from papillomavirus-infected animals produces infections in recipients. Public health implications are significant if the same is true for humans.DefinitionsLocal papillomavirus infection:An infection initiated by the direct application of virus or viral DNA to the site of infectionIntravenous (IV) papillomavirus infection:An infection resulting from blood-borne delivery of virus or viral DNA to the site of infection.

scholarly journals Spatial and Functional Organization of Human Papillomavirus Replication Foci in the Productive Stage of Infection

mBio ◽  
2021 ◽  
Author(s):  
Simran Khurana ◽  
Tovah E. Markowitz ◽  
Juraj Kabat ◽  
Alison A. McBride
Keyword(s):  
Human Papillomavirus ◽  
Persistent Infection ◽  
Chronic Infection ◽  
Functional Organization ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Dna Viruses ◽  
Mucosal Epithelium ◽  
Human Cancers ◽  
Replication Foci

Human papillomaviruses are small DNA viruses that cause chronic infection of cutaneous and mucosal epithelium. In some cases, persistent infection with HPV can result in cancer, and 5% of human cancers are the result of HPV infection.

scholarly journals Prevalence of human papillomavirus infection in rural villages of the Bolivian Amazon

2003 ◽  
Vol 45 (3) ◽  
pp. 131-135 ◽  
Author(s):  
Jorge Cervantes ◽  
Carolina Lema ◽  
Luisa Hurtado ◽  
Ronald Andrade ◽  
Gladys Quiroga ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Infection Prevalence ◽  
Lifestyle Behaviors ◽  
Major Health Problem ◽  
Rural Villages ◽  
Papillomavirus Infection ◽  
Bolivian Amazon ◽  
High Incidence

Cervical cancer constitutes a major health problem in developing countries like Bolivia. The roles of certain genotypes of human papillomaviruses (HPVs) in the pathogenesis of cervical cancer is well established. The prevalence of HPV infection among sexually active women varies greatly. Information regarding HPV infection in Bolivia is very much scarce, specially in regions like the Amazonian lowland. We studied 135 healthy women living in four rural localities of the Bolivian Amazon. Presence of HPV in DNA extracted from cervical swabs was analyzed using a reverse line hybridization assay. The estimated overall HPV infection prevalence among the studied rural localities was 5.9% (ranging from 0-16.6%). These values were unexpectedly low considering Bolivia has a high incidence of cervical cancer. The fact that Amazonian people seem to be less exposed to HPV, makes it likely that some other risk factors including host lifestyle behaviors and genetic background may be involved in the development of cervical cancer in this population.

scholarly journals The Epidemiology of Human Papillomavirus Infection and Cervical Cancer

2007 ◽  
Vol 23 (4) ◽  
pp. 213-227 ◽  
Author(s):  
F. Xavier Bosch ◽  
Silvia de Sanjosé
Keyword(s):  
Cervical Cancer ◽  
Invasive Cervical Cancer ◽  
Intraepithelial Neoplasia ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Transmitted Infection ◽  
Hpv Dna ◽  
Sexually Transmitted ◽  
Papillomavirus Infection ◽  
Simplex Virus

Cervical cancer has been recognized as a rare outcome of a common Sexually Transmitted Infection (STI). The etiologic association is restricted to a limited number of viral types of the family of the Human Papillomaviruses (HPVs). The association is causal in nature and under optimal testing systems, HPV DNA can be identified in all specimens of invasive cervical cancer. As a consequence, it has been claimed that HPV infection is a necessary cause of cervical cancer. The evidence is consistent worldwide and implies both the Squamous Cell Carcinomas (SCC), the adenocarcinomas and the vast majority (i.e. > 95%) of the immediate precursors, namely High Grade Squamous Intraepithelial Lesions (HSIL)/Cervical Intraepithelial Neoplasia 3 (CIN3)/Carcinomain situ. Co-factors that modify the risk among HPV DNA positive women include the use of oral contraceptives (OC) for five or more years, smoking, high parity (five or more full term pregnancies) and previous exposure to other sexually transmitted diseases such as Chlamydia Trachomatis (CT) and Herpes Simplex Virus type 2 (HSV-2). Women exposed to the Human Immunodeficiency Virus (HIV) are at high risk for HPV infection, HPV DNA persistency and progression of HPV lesions to cervical cancer.

scholarly journals The Cytoskeletal Adaptor Obscurin-Like 1 Interacts with the Human Papillomavirus 16 (HPV16) Capsid Protein L2 and Is Required for HPV16 Endocytosis

2016 ◽  
Vol 90 (23) ◽  
pp. 10629-10641 ◽  
Author(s):  
Elena Wüstenhagen ◽  
Laura Hampe ◽  
Fatima Boukhallouk ◽  
Marc A. Schneider ◽  
Gilles A. Spoden ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Capsid Protein ◽  
Viral Entry ◽  
Adaptor Protein ◽  
Hpv Infection ◽  
Host Factor ◽  
Human Papillomaviruses ◽  
Endocytic Pathway ◽  
Target Cells ◽  
Gene Transduction

ABSTRACTThe human papillomavirus (HPV) capsid protein L2 is essential for viral entry. To gain a deeper understanding of the role of L2, we searched for novel cellular L2-interacting proteins. A yeast two-hybrid analysis uncovered the actin-depolymerizing factor gelsolin, the membrane glycoprotein dysadherin, the centrosomal protein 68 (Cep68), and the cytoskeletal adaptor protein obscurin-like 1 protein (OBSL1) as putative L2 binding molecules. Pseudovirus (PsV) infection assays identified OBSL1 as a host factor required for gene transduction by three oncogenic human papillomavirus types, HPV16, HPV18, and HPV31. In addition, we detected OBSL1 expression in cervical tissue sections and noted the involvement of OBSL1 during gene transduction of primary keratinocytes by HPV16 PsV. Complex formation of HPV16 L2 with OBSL1 was demonstrated in coimmunofluorescence and coimmunoprecipitation studies after overexpression of L2 or after PsV exposure. We observed a strong colocalization of OBSL1 with HPV16 PsV and tetraspanin CD151 at the plasma membrane, suggesting a role for OBSL1 in viral endocytosis. Indeed, viral entry assays exhibited a reduction of viral endocytosis in OBSL1-depleted cells. Our results suggest OBSL1 as a novel L2-interacting protein and endocytosis factor in HPV infection.IMPORTANCEHuman papillomaviruses infect mucosal and cutaneous epithelia, and the high-risk HPV types account for 5% of cancer cases worldwide. As recently discovered, HPV entry occurs by a clathrin-, caveolin-, and dynamin-independent endocytosis via tetraspanin-enriched microdomains. At present, the cellular proteins involved in the underlying mechanism of this type of endocytosis are under investigation. In this study, the cytoskeletal adaptor OBSL1 was discovered as a previously unrecognized interaction partner of the minor capsid protein L2 and was identified as a proviral host factor required for HPV16 endocytosis into target cells. The findings of this study advance the understanding of a so far less well-characterized endocytic pathway that is used by oncogenic HPV subtypes.

scholarly journals Current Updates on Cancer-Causing Types of Human Papillomaviruses (HPVs) in East, Southeast, and South Asia

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2691
Author(s):  
Chichao Xia ◽  
Sile Li ◽  
Teng Long ◽  
Zigui Chen ◽  
Paul K. S. Chan ◽  
...  
Keyword(s):  
South Asia ◽  
Head And Neck ◽  
Age Groups ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Diagnostic Methods ◽  
Dna Viruses ◽  
Treatment Regimens ◽  
Hpv Genotypes ◽  
Insight Into

Human papillomavirus (HPV) infection remains one of the most prominent cancer-causing DNA viruses, contributing to approximately 5% of human cancers. While association between HPV and cervical cancers has been well-established, evidence on the attribution of head and neck cancers (HNC) to HPV have been increasing in recent years. Among the cancer-causing HPV genotypes, HPV16 and 18 remain the major contributors to cancers across the globe. Nonetheless, the distribution of HPV genotypes in ethnically, geographically, and socio-economically diverse East, Southeast, and South Asia may differ from other parts of the world. In this review, we garner and provide updated insight into various aspects of HPV reported in recent years (2015–2021) in these regions. We included: (i) the HPV genotypes detected in normal cancers of the uterine cervix and head and neck, as well as the distribution of the HPV genotypes by geography and age groups; (ii) the laboratory diagnostic methods and treatment regimens used within these regions; and (iii) the oncogenic properties of HPV prototypes and their variants contributing to carcinogenesis. More importantly, we also unveil the similarities and discrepancies between these aspects, the areas lacking study, and the challenges faced in HPV studies.

Papillomavirus infection and reproduction

2020 ◽  
Vol 75 (3) ◽  
pp. 189-195
Author(s):  
Vladislav I. Krasnopolsky ◽  
Nina V. Zarochentseva ◽  
Ksenia V. Krasnopolskaya ◽  
Yulia N. Bashankaeva ◽  
Varvara S. Kuzmicheva
Keyword(s):  
Human Papillomavirus ◽  
Hpv Vaccination ◽  
Carcinogenic Risk ◽  
Human Papillomaviruses ◽  
World Health ◽  
Sexually Transmitted ◽  
Associated Diseases ◽  
Trophoblastic Cells ◽  
Papillomavirus Infection ◽  
Health Organization

The purpose of the review a synthesis of research data on the role of human papillomavirus infection in the reproductive health of women and men. Key Points. Human papillomavirus (HPV) is one of the most common sexually transmitted viruses worldwide. According to the World Health Organization, HPV is the main cause of the development of HPV-associated diseases among both women and men. Viruses are subdivided into HPV with low carcinogenic risk, which cause benign warts, and HPV with high carcinogenic risk, which cause cancer. Different types of human papillomaviruses depending on their characteristic tropism, are divided into skin and mucous types. Viral infection in men leads to a decrease in the quality of sperm (for example, asthenozoospermia) due to apoptosis in sperm cells and due to the development of antisperm immunity. A negative viral effect on the fertility of women is manifested in an increase in the frequency of spontaneous miscarriages and a premature rupture of the amniotic membranes during pregnancy. There is evidence that HPV decreases the number of trophoblastic cells and abnormal trophoblastic-endometrial adhesion is also observed. In trophoblastic cells transfected with high-risk HPV, the level of apoptosis increases. HPV vaccination is safe, and the results show not only protection against HPV-associated diseases in women and men, but also a reduction of gestational complications, reduced preterm birth rates and the protection of newborns from infection.

scholarly journals Different Methods in HPV Genotyping of Anogenital and Oropharyngeal Lesions: Comparison between VisionArray® Technology, Next Generation Sequencing, and Hybrid Capture Assay

2021 ◽  
Vol 2 (1) ◽  
pp. 29-41
Author(s):  
Giorgia Acquaviva ◽  
Michela Visani ◽  
Viviana Sanza ◽  
Antonio De Leo ◽  
Thais Maloberti ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Turnaround Time ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Next Generation ◽  
Hybrid Capture ◽  
Capture Assay ◽  
Anogenital Area ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

(1) Background: Human papillomaviruses (HPVs) are known to be related to the development of about 5% of all human cancers. The clinical relevance of HPV infection has been deeply investigated in carcinomas of the oropharyngeal area, uterine cervix, and anogenital area. To date, several different methods have been used for detecting HPV infection. The aim of the present study was to compare three different methods for the diagnosis of the presence of the HPV genome. (2) Methods: A total of 50 samples were analyzed. Twenty-five of them were tested using both next generation sequencing (NGS) and VisionArray® technology, the other 25 were tested using Hybrid Capture (HC) II assay and VisionArray® technology. (3) Results: A substantial agreement was obtained using NGS and VisionArray® (κ = 0.802), as well as between HC II and VisionArray® (κ = 0.606). In both analyses, the concordance increased if only high risk HPVs I(HR-HPVs) were considered as “positive”. (4) Conclusions: Our data highlighted the importance of technical choice in HPV characterization, which should be guided by the clinical aims, costs, starting material, and turnaround time for results.

scholarly journals HPV and Other Microbiota; Who’s Good and Who’s Bad: Effects of the Microbial Environment on the Development of Cervical Cancer—A Non-Systematic Review

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 714
Author(s):  
Matthias Läsche ◽  
Horst Urban ◽  
Julia Gallwas ◽  
Carsten Gründker
Keyword(s):  
Systematic Review ◽  
Cervical Cancer ◽  
High Risk ◽  
Cervical Carcinoma ◽  
Hpv Infection ◽  
Human Papillomaviruses ◽  
Inflammatory Reactions ◽  
Metabolic Signalling ◽  
Microbial Environment ◽  
High Risk Hpv

Cervical cancer is responsible for around 5% of all human cancers worldwide. It develops almost exclusively from an unsolved, persistent infection of the squamocolumnar transformation zone between the endo- and ecto-cervix with various high-risk (HR) human papillomaviruses (HPVs). The decisive turning point on the way to persistent HPV infection and malignant transformation is an immune system weakened by pathobionts and oxidative stress and an injury to the cervical mucosa, often caused by sexual activities. Through these injury and healing processes, HPV viruses, hijacking activated keratinocytes, move into the basal layers of the cervical epithelium and then continue their development towards the distal prickle cell layer (Stratum spinosum). The microbial microenvironment of the cervical tissue determines the tissue homeostasis and the integrity of the protective mucous layer through the maintenance of a healthy immune and metabolic signalling. Pathological microorganisms and the resulting dysbiosis disturb this signalling. Thus, pathological inflammatory reactions occur, which manifest the HPV infection. About 90% of all women contract an HPV infection in the course of their lives. In about 10% of cases, the virus persists and cervical intra-epithelial neoplasia (CIN) develops. Approximately 1% of women with a high-risk HPV infection incur a cervical carcinoma after 10 to 20 years. In this non-systematic review article, we summarise how the sexually and microbial mediated pathogenesis of the cervix proceeds through aberrant immune and metabolism signalling via CIN to cervical carcinoma. We show how both the virus and the cancer benefit from the same changes in the immune and metabolic environment.

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