The molecular biology and HPV drug responsiveness of cynomolgus macaque papillomaviruses support their use in the development of a relevant in vivo model for antiviral drug testing

Tombak, Eva Maria; Männik, Andres; Burk, Robert D.; Grand, Roger Le; Ustav, Ene; Ustav, Mart

doi:10.1371/journal.pone.0211235

Cited by 3 publications

(2 citation statements)

References 82 publications

(169 reference statements)

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“…3225, resulting in E8 residues 1–11 fused to E2 residues 207–410 [ 15 ]. Transcript analyses indicate that animal PV (Macaca fascicularis (Mf) PV1, MfPV5, MfPV8, Mus musculus (Mmu) PV1, Mastomys natalensis (Mn) PV1, Sylvilagus floridanus (Sf) PV1 (or cottontail rabbit) CRPV) as well as HPV1, 5, 8, 11, 16, 18, 31, 33, and 49 express a spliced RNA homologous to the BPV1 E8/E2 mRNA ( Figure 1 ) [ 8 , 14 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ]. Bioinformatic analyses suggest that the potential to generate E8^E2 transcripts and the corresponding fusion proteins is highly conserved, as E8 exons can be found in more than 300 mammalian PV genomes, including all HPV types in the alpha, beta, gamma, and mu-genera [ 19 , 31 ].…”

Section: E2 Repressor Proteinsmentioning

confidence: 99%

Functions of Papillomavirus E8^E2 Proteins in Tissue Culture and In Vivo

Kuehner¹,

Stubenrauch²

2022

Viruses

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Papillomaviruses (PV) replicate in undifferentiated keratinocytes at low levels and to high levels in differentiated cells. The restricted replication in undifferentiated cells is mainly due to the expression of the conserved viral E8^E2 repressor protein, a fusion protein consisting of E8 and the hinge, DNA-binding, and dimerization domain of E2. E8^E2 binds to viral genomes and represses viral transcription and genome replication by recruiting cellular NCoR/SMRT-HDAC3 corepressor complexes. Tissue culture experiments have revealed that E8^E2 modulates long-term maintenance of extrachromosomal genomes, productive replication, and immortalization properties in a virus type-dependent manner. Furthermore, in vivo experiments have indicated that Mus musculus PV1 E8^E2 is required for tumor formation in immune-deficient mice. In summary, E8^E2 is a crucial inhibitor whose levels might determine the outcome of PV infections.

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Section: E2 Repressor Proteinsmentioning

confidence: 99%

Functions of Papillomavirus E8^E2 Proteins in Tissue Culture and In Vivo

Kuehner¹,

Stubenrauch²

2022

Viruses

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“…As HPV16 E7 harbors a strong C57BL/6 epitope [15], the use of this model is likely to lead to an overestimation of the potential to induce anti-tumor efficacy. Macaca Fascicularis with cervical papillomavirus infection also provides a highly relevant model for the treatment of cervical infection [16] but does not address the cancer stages of HPV disease and is also less commonly used due to its availability and ethical concerns.…”

Section: Introductionmentioning

confidence: 99%

Preferential Expansion of HPV16 E1-Specific T Cells from Healthy Donors’ PBMCs after Ex Vivo Immunization with an E1E2E6E7 Fusion Antigen

Daradoumis,

Müller,

Neckermann

et al. 2023

Cancers

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Persistent human papillomavirus (HPV) infection is responsible for practically all cervical and a high proportion of anogenital and oropharyngeal cancers. Therapeutic HPV vaccines in clinical development show great promise in improving outcomes for patients who mount an anti-HPV T-cell response; however, far from all patients elicit a sufficient immunological response. This demonstrates a translational gap between animal models and human patients. Here, we investigated the potential of a new assay consisting of co-culturing vaccine-transduced dendritic cells (DCs) with syngeneic, healthy, human peripheral blood mononuclear cells (PBMCs) to mimic a human in vivo immunization. This new promising human ex vivo PBMC assay was evaluated using an innovative therapeutic adenovirus (Adv)-based HPV vaccine encoding the E1, E2, E6, and E7 HPV16 genes. This new method allowed us to show that vaccine-transduced DCs yielded functional effector T cells and unveiled information on immunohierarchy, showing E1-specific T-cell immunodominance over time. We suggest that this assay can be a valuable translational tool to complement the known animal models, not only for HPV therapeutic vaccines, and supports the use of E1 as an immunotherapeutic target. Nevertheless, the findings reported here need to be validated in a larger number of donors and preferably in patient samples.

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Expression of E8^E2 Is Required for Wart Formation by Mouse Papillomavirus 1 In Vivo

Stubenrauch¹,

Straub²,

Klein³

et al. 2021

J Virol

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Human papillomavirus (HPV) E1 and E2 proteins activate genome replication. E2 also modulates viral gene expression and is involved in the segregation of viral genomes. In addition to full length E2, almost all PV share the ability to encode an E8^E2 protein, that is a fusion of E8 with the C-terminal half of E2 which mediates specific DNA-binding and dimerization. HPV E8^E2 acts as a repressor of viral gene expression and genome replication. To analyze the function of E8^E2 in vivo, we used the Mus musculus PV1 (MmuPV1)-mouse model system. Characterization of the MmuPV1 E8^E2 protein revealed that it inhibits transcription from viral promoters in the absence and presence of E1 and E2 proteins and that this is partially dependent upon the E8 domain. MmuPV1 genomes, in which the E8 ATG start codon was disrupted (E8-), displayed a 10- to 25-fold increase in viral gene expression compared to wt genomes in cultured normal mouse tail keratinocytes in short-term experiments. This suggests that the function and mechanism of E8^E2 is conserved between MmuPV1 and HPVs. Surprisingly, challenge of athymic nude Foxn1nu/nu mice with MmuPV1 E8- genomes did not induce warts on the tail in contrast to wt MmuPV1. Furthermore, viral gene expression was completely absent at E8- MmuPV1 sites 20 - 22 weeks after DNA challenge on the tail or quasivirus challenge in the vaginal vault. This reveals that expression of E8^E2 is necessary to form tumors in vivo and that this is independent from the presence of T-cells. IMPORTANCE HPV encode an E8^E2 protein which acts as repressors of viral gene expression and genome replication. In cultured normal keratinocytes, E8^E2 is essential for long-term episomal maintenance of HPV31 genomes, but not for HPV16. To understand E8^E2's role in vivo, the Mus musculus PV1 (MmuPV1)-mouse model system was used. This revealed that E8^E2's function as a repressor of viral gene expression is conserved. Surprisingly, MmuPV1 E8^E2 knock out genomes did not induce warts in T-cell deficient mice. This shows for the first time that expression of E8^E2 is necessary for tumor formation in vivo independently of T cell immunity. This indicates that E8^E2 could be an interesting target for anti-viral therapy in vivo.

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The molecular biology and HPV drug responsiveness of cynomolgus macaque papillomaviruses support their use in the development of a relevant in vivo model for antiviral drug testing

Cited by 3 publications

References 82 publications

Functions of Papillomavirus E8^E2 Proteins in Tissue Culture and In Vivo

Functions of Papillomavirus E8^E2 Proteins in Tissue Culture and In Vivo

Preferential Expansion of HPV16 E1-Specific T Cells from Healthy Donors’ PBMCs after Ex Vivo Immunization with an E1E2E6E7 Fusion Antigen

Expression of E8^E2 Is Required for Wart Formation by Mouse Papillomavirus 1 In Vivo

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