Mutations in HPV18 E1^E4 Impact Virus Capsid Assembly, Infectivity Competence, and Maturation.

Jennifer Biryukov,Margaret Mclaughlin-Drubin,Janice Milici,Jocelyn Myers,Craig Meyers,Heather Griffin,John Doorbar

doi:10.3390/v9120385

Jennifer Biryukov, Margaret Mclaughlin-Drubin + Show 5 more

Open Access

https://doi.org/10.3390/v9120385

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Abstract

The most highly expressed protein during the productive phase of the human papillomavirus (HPV) life cycle is E1^E4. Its full role during infection remains to be established. HPV E1^E4 is expressed during both the early and late stages of the virus life cycle and contributes to viral genome amplification. In an attempt to further outline the functions of E1^E4, and determine whether it plays a role in viral capsid assembly and viral infectivity, we examined wild-type E1^E4 as well as four E1^E4 truncation mutants. Our study revealed that HPV18 genomes containing the shortest truncated form of E1^E4, the 17/18 mutant, produced viral titers that were similar to wild-type virus and significantly higher compared to virions containing the three longer E1^E4 mutants. Additionally, the infectivity of virus containing the shortest E1^E4 mutation was equivalent to wild-type and significantly higher than the other three mutants. In contrast, infectivity was completely abrogated for virus containing the longer E1^E4 mutants, regardless of virion maturity. Taken together, our results indicate for the first time that HPV18 E1^E4 impacts capsid assembly and viral infectivity as well as virus maturation.

Highlights

Human papillomaviruses (HPVs) are small DNA tumor viruses that have been identified as the etiological agent of cervical cancer [1,2]
This study indicates for the first time that human papillomavirus papillomavirus type-18 type-18 (HPV18) E1ˆE4 may play a role in viral capsid assembly, viral infectivity, and virus maturation
Mutagenesis was carried out using a subgenomic HPV18 genomic fragment that was excised from plasmid pBSSK-HPV18 following digestion with Apa I and cloned into plasmid pBC (Stratagene, Bellingham, WA, USA)

Summary

Introduction

Human papillomaviruses (HPVs) are small DNA tumor viruses that have been identified as the etiological agent of cervical cancer [1,2]. HPVs are associated with other anogenital and oral cancers [3,4,5]. All HPV types infect and replicate exclusively in epithelium, and are subdivided based on their ability to infect either cutaneous or mucosal keratinocytes. HPVs that infect mucosal keratinocytes are further subdivided into low-risk and high-risk types. Low-risk types are associated with benign lesions such as condylomas and warts, with high-risk types causing malignant neoplasms such as cervical cancer [6].

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