Research

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18 pages, 3242 KiB

Open AccessArticle

Surfactant Protein A Impairs Genital HPV16 Pseudovirus Infection by Innate Immune Cell Activation in A Murine Model

by Sylvia Ujma, Sinead Carse, Alisha Chetty, William Horsnell, Howard Clark, Jens Madsen, Rose-Marie Mackay, Alastair Watson, Mark Griffiths, Arieh A. Katz and Georgia Schäfer

Pathogens 2019, 8(4), 288; https://doi.org/10.3390/pathogens8040288 - 06 Dec 2019

Cited by 11 | Viewed by 3505

Abstract

Infection by oncogenic human papillomavirus (HPV) is the principle cause of cervical cancer and other anogenital cancers. The majority of cervical cancer cases occur in low- and middle-income countries (LMIC). Prophylactic vaccines exist to combat HPV infection but accessibility to these in LMIC [...] Read more.

Infection by oncogenic human papillomavirus (HPV) is the principle cause of cervical cancer and other anogenital cancers. The majority of cervical cancer cases occur in low- and middle-income countries (LMIC). Prophylactic vaccines exist to combat HPV infection but accessibility to these in LMIC is limited. Alternative preventative measures against HPV infection are therefore also needed to control cervical cancer risk. HPV employs multiple mechanisms to evade the host immune response. Therefore, an approach to promote HPV recognition by the immune system can reduce infection. Surfactant proteins A and D (SP-A and SP-D) are highly effective innate opsonins of pathogens. Their function is primarily understood in the lung, but they are also expressed at other sites of the body, including the female reproductive tract (FRT). We hypothesized that raised levels of SP-A and/or SP-D may enhance immune recognition of HPV and reduce infection. Co-immunoprecipitation and flow cytometry experiments showed that purified human SP-A protein directly bound HPV16 pseudovirions (HPV16-PsVs), and the resulting HPV16-PsVs/SP-A complex enhanced uptake of HPV16-PsVs by RAW264.7 murine macrophages. In contrast, a recombinant fragment of human SP-D bound HPV16-PsVs weakly and had no effect on viral uptake. To assess if SP-A modulates HPV16-PsVs infection in vivo, a murine cervicovaginal challenge model was applied. Surprisingly, neither naïve nor C57BL/6 mice challenged with HPV16-PsVs expressed SP-A in the FRT. However, pre-incubation of HPV16-PsVs with purified human SP-A at a 1:10 (w/w) ratio significantly reduced the level of HPV16-PsV infection. When isolated cells from FRTs of naïve C57BL/6 mice were incubated with HPV16-PsVs and stained for selected innate immune cell populations by flow cytometry, significant increases in HPV16-PsVs uptake by eosinophils, neutrophils, monocytes, and macrophages were observed over time using SP-A-pre-adsorbed virions compared to control particles. This study is the first to describe a biochemical and functional association of HPV16 virions with the innate immune molecule SP-A. We show that SP-A impairs HPV16-PsVs infection and propose that SP-A is a potential candidate for use in topical microbicides which provide protection against new HPV infections. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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16 pages, 3292 KiB

Open AccessArticle

β-HPV 8E6 Attenuates ATM and ATR Signaling in Response to UV Damage

by Jazmine A. Snow, Vaibhav Murthy, Dalton Dacus, Changkun Hu and Nicholas A. Wallace

Pathogens 2019, 8(4), 267; https://doi.org/10.3390/pathogens8040267 - 26 Nov 2019

Cited by 16 | Viewed by 3216

Abstract

Given the high prevalence of cutaneous genus beta human papillomavirus (β-HPV) infections, it is important to understand how they manipulate their host cells. This is particularly true for cellular responses to UV damage, since our skin is continually exposed to UV. The E6 [...] Read more.

Given the high prevalence of cutaneous genus beta human papillomavirus (β-HPV) infections, it is important to understand how they manipulate their host cells. This is particularly true for cellular responses to UV damage, since our skin is continually exposed to UV. The E6 protein from β-genus HPV (β-HPV E6) decreases the abundance of two essential UV-repair kinases (ATM and ATR). Although β-HPV E6 reduces their availability, the impact on downstream signaling events is unclear. We demonstrate that β-HPV E6 decreases ATM and ATR activation. This inhibition extended to XPA, an ATR target necessary for UV repair, lowering both its phosphorylation and accumulation. β-HPV E6 also hindered POLη accumulation and foci formation, critical steps in translesion synthesis. ATM’s phosphorylation of BRCA1 is also attenuated by β-HPV E6. While there was a striking decrease in phosphorylation of direct ATM/ATR targets, events further down the cascade were not reduced. In summary, despite being incomplete, β-HPV 8E6’s hindrance of ATM/ATR has functional consequences. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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Review

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19 pages, 2086 KiB

Open AccessReview

The Role of Ataxia Telangiectasia Mutant and Rad3-Related DNA Damage Response in Pathogenesis of Human Papillomavirus

by Ying Luo and Shiyuan Hong

Pathogens 2020, 9(6), 506; https://doi.org/10.3390/pathogens9060506 - 23 Jun 2020

Cited by 2 | Viewed by 3785

Abstract

Human papillomavirus (HPV) infection leads to a variety of benign lesions and malignant tumors such as cervical cancer and head and neck squamous cell carcinoma. Several HPV vaccines have been developed that can help to prevent cervical carcinoma, but these vaccines are only [...] Read more.

Human papillomavirus (HPV) infection leads to a variety of benign lesions and malignant tumors such as cervical cancer and head and neck squamous cell carcinoma. Several HPV vaccines have been developed that can help to prevent cervical carcinoma, but these vaccines are only effective in individuals with no prior HPV infection. Thus, it is still important to understand the HPV life cycle and in particular the association of HPV with human pathogenesis. HPV production requires activation of the DNA damage response (DDR), which is a complex signaling network composed of multiple sensors, mediators, transducers, and effectors that safeguard cellular DNAs to maintain the host genome integrity. In this review, we focus on the roles of the ataxia telangiectasia mutant and Rad3-related (ATR) DNA damage response in HPV DNA replication. HPV can induce ATR expression and activate the ATR pathway. Inhibition of the ATR pathway results in suppression of HPV genome maintenance and amplification. The mechanisms underlying this could be through various molecular pathways such as checkpoint signaling and transcriptional regulation. In light of these findings, other downstream mechanisms of the ATR pathway need to be further investigated for better understanding HPV pathogenesis and developing novel ATR DDR-related inhibitors against HPV infection. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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18 pages, 994 KiB

Open AccessEditor’s ChoiceReview

Epigenetic Regulation of the Human Papillomavirus Life Cycle

by Michelle Mac and Cary A. Moody

Pathogens 2020, 9(6), 483; https://doi.org/10.3390/pathogens9060483 - 18 Jun 2020

Cited by 32 | Viewed by 8984

Abstract

Persistent infection with certain types of human papillomaviruses (HPVs), termed high risk, presents a public health burden due to their association with multiple human cancers, including cervical cancer and an increasing number of head and neck cancers. Despite the development of prophylactic vaccines, [...] Read more.

Persistent infection with certain types of human papillomaviruses (HPVs), termed high risk, presents a public health burden due to their association with multiple human cancers, including cervical cancer and an increasing number of head and neck cancers. Despite the development of prophylactic vaccines, the incidence of HPV-associated cancers remains high. In addition, no vaccine has yet been licensed for therapeutic use against pre-existing HPV infections and HPV-associated diseases. Although persistent HPV infection is the major risk factor for cancer development, additional genetic and epigenetic alterations are required for progression to the malignant phenotype. Unlike genetic mutations, the reversibility of epigenetic modifications makes epigenetic regulators ideal therapeutic targets for cancer therapy. This review article will highlight the recent advances in the understanding of epigenetic modifications associated with HPV infections, with a particular focus on the role of these epigenetic changes during different stages of the HPV life cycle that are closely associated with activation of DNA damage response pathways. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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15 pages, 1438 KiB

Open AccessEditor’s ChoiceReview

Activating the DNA Damage Response and Suppressing Innate Immunity: Human Papillomaviruses Walk the Line

by Claire D. James, Dipon Das, Molly L. Bristol and Iain M. Morgan

Pathogens 2020, 9(6), 467; https://doi.org/10.3390/pathogens9060467 - 13 Jun 2020

Cited by 8 | Viewed by 3880

Abstract

Activation of the DNA damage response (DDR) by external agents can result in DNA fragments entering the cytoplasm and activating innate immune signaling pathways, including the stimulator of interferon genes (STING) pathway. The consequences of this activation can result in alterations in the [...] Read more.

Activation of the DNA damage response (DDR) by external agents can result in DNA fragments entering the cytoplasm and activating innate immune signaling pathways, including the stimulator of interferon genes (STING) pathway. The consequences of this activation can result in alterations in the cell cycle including the induction of cellular senescence, as well as boost the adaptive immune response following interferon production. Human papillomaviruses (HPV) are the causative agents in a host of human cancers including cervical and oropharyngeal; HPV are responsible for around 5% of all cancers. During infection, HPV replication activates the DDR in order to promote the viral life cycle. A striking feature of HPV-infected cells is their ability to continue to proliferate in the presence of an active DDR. Simultaneously, HPV suppress the innate immune response using a number of different mechanisms. The activation of the DDR and suppression of the innate immune response are essential for the progression of the viral life cycle. Here, we describe the mechanisms HPV use to turn on the DDR, while simultaneously suppressing the innate immune response. Pushing HPV from this fine line and tipping the balance towards activation of the innate immune response would be therapeutically beneficial. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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16 pages, 2368 KiB

Open AccessEditor’s ChoiceReview

The Relationship between Estrogen-Related Signaling and Human Papillomavirus Positive Cancers

by Claire D. James, Iain M. Morgan and Molly L. Bristol

Pathogens 2020, 9(5), 403; https://doi.org/10.3390/pathogens9050403 - 22 May 2020

Cited by 22 | Viewed by 6399

Abstract

High risk-human papillomaviruses (HPVs) are known carcinogens. Numerous reports have linked the steroid hormone estrogen, and the expression of estrogen receptors (ERs), to HPV-related cancers, although the exact nature of the interactions remains to be fully elucidated. Here we will focus on estrogen [...] Read more.

High risk-human papillomaviruses (HPVs) are known carcinogens. Numerous reports have linked the steroid hormone estrogen, and the expression of estrogen receptors (ERs), to HPV-related cancers, although the exact nature of the interactions remains to be fully elucidated. Here we will focus on estrogen signaling and describe both pro and potentially anti-cancer effects of this hormone in HPV-positive cancers. This review will summarize: (1) cell culture-related evidence, (2) animal model evidence, and (3) clinical evidence demonstrating an interaction between estrogen and HPV-positive cancers. This comprehensive review provides insights into the potential relationship between estrogen and HPV. We suggest that estrogen may provide a potential therapeutic for HPV-related cancers, however additional studies are necessary. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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20 pages, 1295 KiB

Open AccessEditor’s ChoiceReview

Subversion of Host Innate Immunity by Human Papillomavirus Oncoproteins

by Irene Lo Cigno, Federica Calati, Silvia Albertini and Marisa Gariglio

Pathogens 2020, 9(4), 292; https://doi.org/10.3390/pathogens9040292 - 17 Apr 2020

Cited by 38 | Viewed by 6360

Abstract

The growth of human papillomavirus (HPV)-transformed cells depends on the ability of the viral oncoproteins E6 and E7, especially those from high-risk HPV16/18, to manipulate the signaling pathways involved in cell proliferation, cell death, and innate immunity. Emerging evidence indicates that E6/E7 inhibition [...] Read more.

The growth of human papillomavirus (HPV)-transformed cells depends on the ability of the viral oncoproteins E6 and E7, especially those from high-risk HPV16/18, to manipulate the signaling pathways involved in cell proliferation, cell death, and innate immunity. Emerging evidence indicates that E6/E7 inhibition reactivates the host innate immune response, reversing what until then was an unresponsive cellular state suitable for viral persistence and tumorigenesis. Given that the disruption of distinct mechanisms of immune evasion is an attractive strategy for cancer therapy, the race is on to gain a better understanding of E6/E7-induced immune escape and cancer progression. Here, we review recent literature on the interplay between E6/E7 and the innate immune signaling pathways cGAS/STING/TBK1, RIG-I/MAVS/TBK1, and Toll-like receptors (TLRs). The overall emerging picture is that E6 and E7 have evolved broad-spectrum mechanisms allowing for the simultaneous depletion of multiple rather than single innate immunity effectors. The cGAS/STING/TBK1 pathway appears to be the most heavily impacted, whereas the RIG-I/MAVS/TBK1, still partially functional in HPV-transformed cells, can be activated by the powerful RIG-I agonist M8, triggering the massive production of type I and III interferons (IFNs), which potentiates chemotherapy-mediated cell killing. Overall, the identification of novel therapeutic targets to restore the innate immune response in HPV-transformed cells could transform the way HPV-associated cancers are treated. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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17 pages, 1185 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis

by Surendra Sharma and Karl Munger

Pathogens 2020, 9(4), 289; https://doi.org/10.3390/pathogens9040289 - 15 Apr 2020

Cited by 22 | Viewed by 5793

Abstract

Infections with high-risk human papillomaviruses cause ~5% of all human cancers. E6 and E7 are the only viral genes that are consistently expressed in cancers, and they are necessary for tumor initiation, progression, and maintenance. E6 and E7 encode small proteins that lack [...] Read more.

Infections with high-risk human papillomaviruses cause ~5% of all human cancers. E6 and E7 are the only viral genes that are consistently expressed in cancers, and they are necessary for tumor initiation, progression, and maintenance. E6 and E7 encode small proteins that lack intrinsic enzymatic activities and they function by binding to cellular regulatory molecules, thereby subverting normal cellular homeostasis. Much effort has focused on identifying protein targets of the E6 and E7 proteins, but it has been estimated that ~98% of the human transcriptome does not encode proteins. There is a growing interest in studying noncoding RNAs as biochemical targets and biological mediators of human papillomavirus (HPV) E6/E7 oncogenic activities. This review focuses on HPV E6/E7 targeting cellular long noncoding RNAs, a class of biologically versatile molecules that regulate almost every known biological process and how this may contribute to viral oncogenesis. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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11 pages, 698 KiB

Open AccessFeature PaperReview

Papillomaviruses Go Retro

by Jian Xie, Pengwei Zhang, Mac Crite and Daniel DiMaio

Pathogens 2020, 9(4), 267; https://doi.org/10.3390/pathogens9040267 - 07 Apr 2020

Cited by 14 | Viewed by 3625

Abstract

Human papillomaviruses are important pathogens responsible for approximately 5% of cancer as well as other important human diseases, but many aspects of the papillomavirus life cycle are poorly understood. To undergo genome replication, HPV DNA must traffic from the cell surface to the [...] Read more.

Human papillomaviruses are important pathogens responsible for approximately 5% of cancer as well as other important human diseases, but many aspects of the papillomavirus life cycle are poorly understood. To undergo genome replication, HPV DNA must traffic from the cell surface to the nucleus. Recent findings have revolutionized our understanding of HPV entry, showing that it requires numerous cellular proteins and proceeds via a series of intracellular membrane-bound vesicles that comprise the retrograde transport pathway. This paper reviews the evidence supporting this unique entry mechanism with a focus on the crucial step by which the incoming virus particle is transferred from the endosome into the retrograde pathway. This new understanding provides novel insights into basic cellular biology and suggests novel rational approaches to inhibit HPV infection. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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27 pages, 923 KiB

Open AccessEditor’s ChoiceReview

HPV Oncoproteins and the Ubiquitin Proteasome System: A Signature of Malignancy?

by Anamaria Đukić, Lucija Lulić, Miranda Thomas, Josipa Skelin, Nathaniel Edward Bennett Saidu, Magdalena Grce, Lawrence Banks and Vjekoslav Tomaić

Pathogens 2020, 9(2), 133; https://doi.org/10.3390/pathogens9020133 - 18 Feb 2020

Cited by 26 | Viewed by 5097

Abstract

Human papillomavirus (HPV) E6 and E7 oncoproteins are critical for development and maintenance of the malignant phenotype in HPV-induced cancers. These two viral oncoproteins interfere with a plethora of cellular pathways, including the regulation of cell cycle and the control of apoptosis, which [...] Read more.

Human papillomavirus (HPV) E6 and E7 oncoproteins are critical for development and maintenance of the malignant phenotype in HPV-induced cancers. These two viral oncoproteins interfere with a plethora of cellular pathways, including the regulation of cell cycle and the control of apoptosis, which are critical in maintaining normal cellular functions. E6 and E7 bind directly with certain components of the Ubiquitin Proteasome System (UPS), enabling them to manipulate a number of important cellular pathways. These activities are the means by which HPV establishes an environment supporting the normal viral life cycle, however in some instances they can also lead to the development of malignancy. In this review, we have discussed how E6 and E7 oncoproteins from alpha and beta HPV types interact with the components of the UPS, and how this interplay contributes to the development of cancer. Full article

(This article belongs to the Special Issue Viral-host interactions and determinants of human papillomavirus (HPV) life cycle and pathogenesis)

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