A prospective study on the natural course of low‐grade squamous intraepithelial lesions and the presence of HPV16 E2‐, E6‐ and E7‐specific T‐cell responses

Woo, Yin Ling; Hende, Muriel van den; Sterling, Jane; Coleman, Nicholas; Crawford, Robin; Kwappenberg, Kitty M. C.; Stanley, Margaret; Burg, Sjoerd H. van der

doi:10.1002/ijc.24804

Cited by 95 publications

(98 citation statements)

References 51 publications

(83 reference statements)

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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.…”

mentioning

confidence: 99%

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Warren

Guo

et al. 2015

J Virol

172

203

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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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mentioning

confidence: 99%

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Warren

Guo

et al. 2015

J Virol

172

203

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“…There are very few studies addressing the issue of lesion progression in relation to tissue immunity: in one study, regression of HSIL is related to lower numbers of stromal CD138+ plasma cells [59], whereas in another, macrophage density seems to increase in persistent or progressing LSIL in comparison to regressing ones [18]. On the other hand, assessment of systemic immunity has so far yielded controversial results: whereas one study shows that immune responses quantified by ELISPOT assays in peripheral blood do not predict regression of HSIL [60], another shows HPV16 E2-and E6-specific T lymphocyte responses (quantified by interferon-gamma ELISPOT) to correlate with progression or persistence of LSIL [61].…”

Section: Discussionmentioning

confidence: 99%

“…Data obtained in each analysis were processed automatically by the system. CLART ® HPV 2 kit allowed the detection of infection and coinfection of 35 different HPV genotypes, namely 6,11,16,18,26,31,33,35,39,40,42,43,44,45,51,52,53,54,56,58,59,61,62,66,68,70,71,72,73,81,82,83,84, 85 and 89 [24]. Diagnostic sensitivity and specificity of the CLART ® HPV 2 kit amount to 98.2% and 100% respectively, according to the manufacturer.…”

Section: Hpv Genotypingmentioning

confidence: 99%

B-lymphocyte, Macrophage and Mast Cell Density in the Stroma Underlying HPV-Related Cervical Squamous Epithelial Lesions and their Relationship to Disease Severity: an Immunohistochemical Study

Foukas¹,

Zourla²,

Tsiodras³

et al. 2012

J Clinic Experiment Pathol

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“…This kind of immune response promotes the regression of the lesion, accompanied or followed by seroconversion with neutralizing antibody production for the major capsid protein L1. 38 Only a minority -estimated to be between 10% and 20% -of infected individuals do not effectively clear the virus. They remain DNA-positive with a persistent active viral infection, and it is these individuals who are at risk for progression to high-grade precancers in the cervix: cervical intraepithelial neoplasia (CIN2/3) and invasive cancer.…”

Section: Natural History Of Hpv Infectionmentioning

confidence: 99%

Biology and natural history of human papillomavirus infection

Fernandes¹,

Araújo²,

Fernandes³

2013

OAJCT

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Human papillomavirus (HPV) is one of the most common causes of sexually transmitted diseases worldwide. It has been proposed that the great majority of women and men have been infected with HPV at least once during their lifetime. HPV infection is associated with a variety of clinical conditions, ranging from benign lesions to cervical cancer. In most cases, the infection is transient, where most of the individuals are healing, eliminating the virus without the presence of any clinical manifestation. Actually, more than 120 HPV types have been cataloged, of which approximately 40 can infect the mucosa of the anogenital tract and are collectively known as mucosal HPV, which are classified based on their oncogenic potential as either low-or high-risk HPV types. The low-risk HPV type causes benign hyperproliferative lesions or genital warts, with a very limited tendency for malignant progression, while the high-risk HPV type is strongly associated with premalignant and malignant cervical lesions. The HPV cycle initiates when the virus gains access to undifferentiated cells of the basement membrane of the squamous columnar junction epithelium of the ectocervix, after these regions are exposed to mechanical or chemical trauma. The basal cells in the transformation zone retain the ability to differentiate, a property required for virion production. Cervical infection with high-risk HPV typically lasts from 12 to 18 months and in most cases is cleared spontaneously. However, in some women the immune response is insufficient to eliminate the virus, resulting in a persistent, long-term infection that may progress to a malignant lesion. In this review, we discuss the biology and natural history of HPV infection and its association with cervical cancer.

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A prospective study on the natural course of low‐grade squamous intraepithelial lesions and the presence of HPV16 E2‐, E6‐ and E7‐specific T‐cell responses

Cited by 95 publications

References 51 publications

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

B-lymphocyte, Macrophage and Mast Cell Density in the Stroma Underlying HPV-Related Cervical Squamous Epithelial Lesions and their Relationship to Disease Severity: an Immunohistochemical Study

Biology and natural history of human papillomavirus infection

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