Epithelial Cell Responses to Infection with Human Papillomavirus

Stanley, Margaret

doi:10.1128/cmr.05028-11

Cited by 352 publications

(302 citation statements)

References 76 publications

(74 reference statements)

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“…Most HPV infections are asymptomatic, or they manifest as benign lesions or warts. They are usually transient and are eventually cleared by the immune system (3). Despite this, HPVs cause a high burden of clinically significant disease worldwide, because the anogenital mucosa-infective high-risk group of HPVs (HR-HPVs) can cause persistent infection that leads to epithelial dysplasia and neoplasia.…”

mentioning

confidence: 99%

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Graham

2016

J Virol

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The human papillomavirus (HPV) life cycle is tightly linked to differentiation of the infected epithelium. This means that viral proteins must exert control over epithelial gene expression in order to optimize viral production. The HPV E2 protein controls replication, transcription, and viral genome partitioning during the viral infectious life cycle. It consists of a nucleic acid-binding domain and a protein-protein interaction domain separated by a flexible serine and arginine-rich hinge region. Over the last few years, mounting evidence has uncovered an important new role for E2 in viral and cellular RNA processing. This Gem discusses the role of E2 in controlling the epithelial cellular environment and how E2 might act to coordinate late events in the viral replication cycle. HUMAN PAPILLOMAVIRUS LIFE CYCLEH uman papillomaviruses (HPVs) are small (ϳ8.0-kbp) circular double-stranded DNA viruses that infect epithelial cells (keratinocytes) (1). There are more than 200 HPV genotypes. For the most part, HPVs of the ␣-genotype group infect mucosal epithelia, while the ␤-genotypes infect predominantly cutaneous epithelia (2). Most HPV infections are asymptomatic, or they manifest as benign lesions or warts. They are usually transient and are eventually cleared by the immune system (3). Despite this, HPVs cause a high burden of clinically significant disease worldwide, because the anogenital mucosa-infective high-risk group of HPVs (HR-HPVs) can cause persistent infection that leads to epithelial dysplasia and neoplasia. HR-HPVs are commonly associated with cervical cancer and tumors of other anogenital sites (2). Per annum, worldwide, there are around 500,000 new cases of cervical disease, and around 270,000 women die from cervical cancer. The two most prevalent HR-HPVs are HPV16 and -18, which are targeted by the current HPV vaccines (4). Over the last few decades, epidemic HR-HPV infection, especially in men, has been associated with a significant increase in oropharyngeal cancers (5). Certain cutaneous HPVs can also cause tumors (squamous cell carcinomas) in immunocompromised or immunosuppressed individuals (6). Thus, the causative association of HPV infection with a number of significant cancers indicates that increased understanding of the viral life cycle is essential.The HPV life cycle is intimately linked to epithelial differentiation (Fig. 1A) (2). HPV normally infects dividing cells at the base of the epithelium (basal layer) but completes its life cycle by amplifying progeny DNA genomes in the midepithelial layers (spinous layer) and carrying out viral encapsidation in the uppermost epithelial layer (granular layer) (Fig. 1A). Viral production is achieved through a highly orchestrated and complex viral gene expression program (Fig. 1A) (2). Mature virions are released upon shedding and disintegration of dead superficial epithelial cells into the environment. As a necessity, HPV infection alters the normal differentiation pattern of the epithelium and controls cellular gene expression to support viral re...

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confidence: 99%

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Graham

2016

J Virol

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“…In addition to their ability to promote cellular transformation, oncogenic viruses have developed mechanisms to target cellular pathways related to innate and adaptive immune surveillance (12)(13)(14)(15)(16)(17). It is believed that these properties facilitate the establishment of a persistent/chronic infection, a key step in virus-mediated carcinogenesis.…”

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confidence: 99%

The T Antigen Locus of Merkel Cell Polyomavirus Downregulates Human Toll-Like Receptor 9 Expression

Sattar

Shuda

Gheit

et al. 2013

J Virol

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“…This suggests that host immune responses may efficiently eliminate most HPV infections. Cell-mediated immune responses may confer protection, as a fraction of patients with HPV16-associated lesions show T cell responses specific to HPV16 E2 and E6 (7)(8)(9)(10). Because HPV infection rarely triggers viremia and strong adaptive immune responses (11), it is believed that innate immune responses also play a critical role in viral clearance.…”

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confidence: 99%

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Warren

Guo

et al. 2015

J Virol

168

187

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Human papillomaviruses (HPVs) are small DNA viruses causally associated with benign warts and multiple cancers, including cervical and head-and-neck cancers. While the vast majority of people are exposed to HPV, most instances of infection are cleared naturally. However, the intrinsic host defense mechanisms that block the early establishment of HPV infections remain mysterious. Several antiviral cytidine deaminases of the human APOBEC3 (hA3) family have been identified as potent viral DNA mutators. While editing of HPV genomes in benign and premalignant cervical lesions has been demonstrated, it remains unclear whether hA3 proteins can directly inhibit HPV infection. Interestingly, recent studies revealed that HPV-positive cervical and head-and-neck cancers exhibited higher rates of hA3 mutation signatures than most HPV-negative cancers. Here, we report that hA3A and hA3B expression levels are highly upregulated in HPV-positive keratinocytes and cervical tissues in early stages of cancer progression, potentially through a mechanism involving the HPV E7 oncoprotein. HPV16 virions assembled in the presence of hA3A, but not in the presence of hA3B or hA3C, have significantly decreased infectivity compared to HPV virions assembled without hA3A or with a catalytically inactive mutant, hA3A/E72Q. Importantly, hA3A knockdown in human keratinocytes results in a significant increase in HPV infectivity. Collectively, our findings suggest that hA3A acts as a restriction factor against HPV infection, but the induction of this restriction mechanism by HPV may come at a cost to the host by promoting cancer mutagenesis. IMPORTANCEHuman papillomaviruses (HPVs) are highly prevalent and potent human pathogens that cause >5% of all human cancers, including cervical and head-and-neck cancers. While the majority of people become infected with HPV, only 10 to 20% of infections are established as persistent infections. This suggests the existence of intrinsic host defense mechanisms that inhibit viral persistence. Using a robust method to produce infectious HPV virions, we demonstrate that hA3A, but not hA3B or hA3C, can significantly inhibit HPV infectivity. Moreover, hA3A and hA3B were coordinately induced in HPV-positive clinical specimens during cancer progression, likely through an HPV E7 oncoprotein-dependent mechanism. Interestingly, HPV-positive cervical and head-and-neck cancer specimens were recently shown to harbor significant amounts of hA3 mutation signatures. Our findings raise the intriguing possibility that the induction of this host restriction mechanism by HPV may also trigger hA3A-and hA3B-induced cancer mutagenesis. Human papillomaviruses (HPVs) are small, nonenveloped DNA viruses known as one of the most prevalent sexually transmitted pathogens. Among almost 200 different genotypes, ϳ24 high-risk HPV genotypes are causally associated with multiple human cancers, including nearly all cervical cancers and a portion of head-and-neck squamous cell carcinomas (1). From 1988 to 2004, the incidence of HPV-associ...

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Epithelial Cell Responses to Infection with Human Papillomavirus

Cited by 352 publications

References 76 publications

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

Human Papillomavirus E2 Protein: Linking Replication, Transcription, and RNA Processing

The T Antigen Locus of Merkel Cell Polyomavirus Downregulates Human Toll-Like Receptor 9 Expression

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

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