Regulation of human papillomavirus gene expression by splicing and polyadenylation

Department of Laboratory Medicine, Section of Medical Microbiology, Lund University, BMC-B13, room B1314c, 221 84 Lund, Sweden.
Nature Reviews Microbiology (Impact Factor: 23.57). 03/2013; 11(4). DOI: 10.1038/nrmicro2984
Source: PubMed


Human papillomaviruses (HPVs) are small DNA tumour viruses that are present in more than 99% of all cervical cancers. The ability of these viruses to cause disease is partly attributed to the strict coordination of viral gene expression with the differentiation stage of the infected cell. HPV gene expression is regulated temporally at the level of RNA splicing and polyadenylation, and a dysregulated gene expression programme allows some HPV types to establish long-term persistence, which is a risk factor for cancer. In this Review, we summarize the role of splicing and polyadenylation in the regulation of HPV gene expression and discuss the viral and cellular factors that control these processes.

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    • "Here we encapsidated a vector expressing firefly luciferase (pY-luc) into HPV PsV because of this reporter's low background, high sensitivity and utility in the mouse challenge model [35]. Recombinant mammalian expression of papillomavirus capsid genes is dramatically enhanced by their codon modification [40], [41], presumably reflecting the disruption of negative regulatory sequences [42]. Several PsV vectors have been previously described [39], [43], [44], [45], [46] and we generated constructs for additional HPV types that were not previously available (Sequences in Table S1 and constructs may be obtained from Addgene ( "
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    ABSTRACT: The licensed human papillomavirus (HPV) vaccines elicit type-restricted immunity but do not target cutaneous HPV types of the beta genus that are associated with non-melanoma skin cancer in immune-compromised patients, and it is unclear if these diverse types share a common mechanism of infection. Residues 11-88 of minor capsid protein L2 contain cross-protective epitopes, and vaccination with concatamers of this region derived from as many as eight alpha HPV (L2 α11-88x8) is being developed as an alternative prophylactic vaccine with potentially broader efficacy. There is also interest in developing broadly protective topical microbicides, such as carrageenan or heparin that block HPV receptor interactions, or small molecule inhibitors of infection. Here we have examined several inhibitors of HPV infection and antisera to L2 α11-88x8 for their breadth of activity against infection by 34 HPV types from within both the alpha and beta families using pseudovirions (PsV) carrying a luciferase reporter as surrogates for native virus. We observed that both heparin and carrageenan prevented infection by mucosatropic HPV types, but surprisingly PsV of several epidermotropic alpha4 and beta HPV types exhibited increased infectivity especially at low inhibitor concentrations. Furin and γ-secretase inhibitors and L2 α11-88x8 antiserum blocked infection by all HPV PsV types tested. These findings suggest that the distinct tropism of mucosal and cutaneous HPV may reflect distinct cell surface receptor interactions, but a common uptake mechanism dependent upon furin and γ-secretase proteolytic activities. Carrageenan, which is being tested as a vaginal microbicide, broadly inhibited infection by the high-risk mucosatropic HPV PsV, but not most skin tropic alpha and beta HPV. Vaccination with an L2 multimer derived exclusively from alpha papillomavirus sequences induced antibodies that broadly neutralized PsV of all 34 HPVs from within both the alpha and beta families, suggesting each displays conserved L2 neutralizing epitopes.
    Full-text · Article · May 2014 · PLoS ONE
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    • "The efficiency by which a splice site is used is determined by cis-acting regulatory RNA elements termed splicing enhancers and silencers (20). We have identified a strong splicing enhancer located downstream of HPV-16 3′-splice site SA3358 (19,21,22), the most commonly used splice site on the HPV-16 genome (23–26). Splice site SA3358 is used by both early and late HPV-16 mRNAs and is regulated by ASF/SF2 (SRSF1) (22), SRp30c (SRSF9) (27) and SRp20 (SRSF3) (28). "
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    ABSTRACT: Human papillomavirus type 16 (HPV-16) 5'-splice site SD3632 is used exclusively to produce late L1 mRNAs. We identified a 34-nt splicing inhibitory element located immediately upstream of HPV-16 late 5'-splice site SD3632. Two AUAGUA motifs located in these 34 nt inhibited SD3632. Two nucleotide substitutions in each of the HPV-16 specific AUAGUA motifs alleviated splicing inhibition and induced late L1 mRNA production from episomal forms of the HPV-16 genome in primary human keratinocytes. The AUAGUA motifs bind specifically not only to the heterogeneous nuclear RNP (hnRNP) D family of RNA-binding proteins including hnRNP D/AUF, hnRNP DL and hnRNP AB but also to hnRNP A2/B1. Knock-down of these proteins induced HPV-16 late L1 mRNA expression, and overexpression of hnRNP A2/B1, hnRNP AB, hnRNP DL and the two hnRNP D isoforms hnRNP D37 and hnRNP D40 further suppressed L1 mRNA expression. This inhibition may allow HPV-16 to hide from the immune system and establish long-term persistent infections with enhanced risk at progressing to cancer. There is an inverse correlation between expression of hnRNP D proteins and hnRNP A2/B1 and HPV-16 L1 production in the cervical epithelium, as well as in cervical cancer, supporting the conclusion that hnRNP D proteins and A2/B1 inhibit HPV-16 L1 mRNA production.
    Full-text · Article · Sep 2013 · Nucleic Acids Research
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    ABSTRACT: The Brd4 protein is an epigenetic reader that is central to regulation of cellular transcription and mitotic bookmarking. The transcription and replication proteins of many viruses interact with Brd4. We describe the multiple roles of Brd4 in the papillomavirus lifecycle.
    Full-text · Article · Jun 2013 · Viruses
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