Secondary Infections, Expanded Tissue Tropism, and Evidence for Malignant Potential in Immunocompromised Mice Infected with Mus musculus Papillomavirus 1 DNA and Virus

Cladel, Nancy M.; Budgeon, Lynn R.; Cooper, Timothy K.; Balogh, Karla K.; Hu, Jiafen; Christensen, Neil D.

doi:10.1128/jvi.00777-13

Cited by 60 publications

(102 citation statements)

References 15 publications

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“…In agreement with a recent report (15), autoinoculation was observed in some mice, implying that minor abrasions and trauma can facilitate the spread of MusPV1. On the muzzle, papillomas occasionally arose not only at the inoculation site (the mucocutaneous border right below the lower lip) but also on the upper lip (best seen in Fig.…”

Section: Discussionsupporting

confidence: 79%

“…The papillomas showed typical histologic features of PV-associated lesions and expressed PV group-specific antigens. A recent report has confirmed the ability of the MusPV1 genome to induce papillomas in Foxn1 nu /Foxn1 nu mice (15). The presence of large arrays of virus particles in lesional keratinocytes (13,14), together with the recent identification of an MusPV1 variant, displaying 99% nucleotide identity to the original MusPV1, in normal skin from a German house mouse (8), supports the conclusion that MusPV1 is a bona fide domestic mouse virus.…”

supporting

confidence: 51%

“…Since PsV carry out the early entry steps in the PV life cycle, these results strongly suggest that region-specific differences in an intracellular factor(s) may be responsible for the observed resistance of the back to papilloma formation by native MusPV1. In a recent publication, Cladel et al (15) used the backs of mice as the primary site of MusPV1 inoculation. In contrast to our results, these authors reported the development of visible lesions on the back that diminished over time.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of Mus musculus Papillomavirus 1 Infection In Situ Reveals an Unusual Pattern of Late Gene Expression and Capsid Protein Localization

Handisurya

Day

Thompson

et al. 2013

J Virol

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Full-length genomic DNA of the recently identified laboratory mouse papillomavirus 1 (MusPV1) was synthesized in vitro and was used to establish and characterize a mouse model of papillomavirus pathobiology. MusPV1 DNA, whether naked or encapsidated by MusPV1 or human papillomavirus 16 (HPV 16) capsids, efficiently induced the outgrowth of papillomas as early as 3 weeks after application to abraded skin on the muzzles and tails of athymic NCr nude mice. High concentrations of virions were extracted from homogenized papillomatous tissues and were serially passaged for >10 generations. Neutralization by L1 antisera confirmed that infectious transmission was capsid mediated. Unexpectedly, the skin of the murine back was much less susceptible to virion-induced papillomas than the muzzle or tail. Although reporter pseudovirions readily transduced the skin of the back, infection with native MusPV1 resulted in less viral genome amplification and gene expression on the back, including reduced expression of the L1 protein and very low expression of the L2 protein, results that imply skin region-specific control of postentry aspects of the viral life cycle. Unexpectedly, L1 protein on the back was predominantly cytoplasmic, while on the tail the abundant L1 was cytoplasmic in the lower epithelial layers and nuclear in the upper layers. Nuclear localization of L1 occurred only in cells that coexpressed the minor capsid protein, L2. The pattern of L1 protein staining in the infected epithelium suggests that L1 expression occurs earlier in the MusPV1 life cycle than in the life cycle of high-risk HPV and that virion assembly is regulated by a previously undescribed mechanism.

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Section: Discussionsupporting

confidence: 79%

supporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

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Characterization of Mus musculus Papillomavirus 1 Infection In Situ Reveals an Unusual Pattern of Late Gene Expression and Capsid Protein Localization

Handisurya

Day

Thompson

et al. 2013

J Virol

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“…To test whether endogenous mA3 expression affects MmuPV1 infection, the tails of three wild-type C57BL/6J (B6) and three B6 Apobec3 knockout (B6 Apobec3 Ϫ/Ϫ ) mice were inoculated with MmuPV1, and tumor formation was monitored for 12 weeks. Three athymic Ncr-nu/nu (nude) mice, which are susceptible to MmuPV1 infection, were used as positive controls (59). While all of the nude mice infected with MmuPV1 showed clearly visible papillomas by 6 weeks, none of wild-type B6 and B6 Apobec3 Ϫ/Ϫ mice developed papillomas (data not shown).…”

Section: Resultsmentioning

confidence: 99%

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Warren

Guo

et al. 2015

J Virol

171

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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“…It has been argued that accelerated carcinogenesis is not adaptive because cells in higher-grade lesions do not produce fully assembled virions [2]. However, given that animal models can be infected with DNA plasmids to produce robust, productive infections [55,56], how infectious are keratinocytes containing HPV DNA? Even if cancer cells themselves are not infectious, how infectious are the cells in the lesions leading up to cancer?…”

Section: Discussionmentioning

confidence: 99%

Could the human papillomavirus vaccines drive virulence evolution?

2015

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The human papillomavirus (HPV) vaccines hold great promise for preventing several cancers caused by HPV infections. Yet little attention has been given to whether HPV could respond evolutionarily to the new selection pressures imposed on it by the novel immunity response created by the vaccine. Here, we present and theoretically validate a mechanism by which the vaccine alters the transmission-recovery trade-off that constrains HPV's virulence such that higher oncogene expression is favoured. With a high oncogene expression strategy, the virus is able to increase its viral load and infected cell population before clearance by the vaccine, thus improving its chances of transmission. This new rapid cell-proliferation strategy is able to circulate between hosts with medium to high turnover rates of sexual partners. We also discuss the importance of better quantifying the duration of challenge infections and the degree to which a vaccinated host can shed virus. The generality of the models presented here suggests a wider applicability of this mechanism, and thus highlights the need to investigate viral oncogenicity from an evolutionary perspective.

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Secondary Infections, Expanded Tissue Tropism, and Evidence for Malignant Potential in Immunocompromised Mice Infected with Mus musculus Papillomavirus 1 DNA and Virus

Cited by 60 publications

References 15 publications

Characterization of Mus musculus Papillomavirus 1 Infection In Situ Reveals an Unusual Pattern of Late Gene Expression and Capsid Protein Localization

Characterization of Mus musculus Papillomavirus 1 Infection In Situ Reveals an Unusual Pattern of Late Gene Expression and Capsid Protein Localization

APOBEC3A Functions as a Restriction Factor of Human Papillomavirus

Could the human papillomavirus vaccines drive virulence evolution?

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