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Preclinical infection model systems are extremely valuable tools to aid in our understanding of Human Papillomavirus (HPV) biology, disease progression, prevention, and treatments. In this context, rodent papillomaviruses and their respective infection models are useful tools but remain underutilized resources in the field of papillomavirus biology...
Similar publications
Preclinical model systems to study multiple features of the papillomavirus life cycle are extremely valuable tools to aid our understanding of Human Papillomavirus (HPV) biology, disease progression and treatments. Mouse papillomavirus (MmuPV1) is the first ever rodent papillomavirus that can infect the laboratory strain of mice and was discovered...
Citations
... 39 [Color figure can be viewed in the online issue, which is available at www. laryngoscope.com.] [32][33][34][35] and were crucial for HPV vaccine development. [36][37][38] Modeling laryngeal disease is an emerging area of study. ...
Objective:
Laryngeal human papillomavirus (HPV) infection causes recurrent respiratory papillomatosis (RRP) and accounts for up to 25% of laryngeal cancers. Lack of satisfactory preclinical models is one reason that treatments for these diseases are limited. We sought to assess the literature describing preclinical models of laryngeal papillomavirus infection.
Data sources:
PubMed, Web of Science, and Scopus were searched from the inception of database through October 2022.
Review methods:
Studies searched were screened by two investigators. Eligible studies were peer-reviewed, published in English, presented original data, and described attempted models of laryngeal papillomavirus infection. Data examined included type of papillomavirus, infection model, and results including success rate, disease phenotype, and viral retention.
Results:
After screening 440 citations and 138 full-text studies, 77 studies published between 1923 and 2022 were included. Models used low-risk HPV or RRP (n = 51 studies), high-risk HPV or laryngeal cancer (n = 16), both low- and high-risk HPV (n = 1), and animal papillomaviruses (n = 9). For RRP, 2D and 3D cell culture models and xenografts retained disease phenotypes and HPV DNA in the short term. Two laryngeal cancer cell lines were consistently HPV-positive in multiple studies. Animal laryngeal infections with animal papillomaviruses resulted in disease and long-term retention of viral DNA.
Conclusions:
Laryngeal papillomavirus infection models have been researched for 100 years and primarily involve low-risk HPV. Most models lose viral DNA after a short duration. Future work is needed to model persistent and recurrent diseases, consistent with RRP and HPV-positive laryngeal cancer.
Level of evidence:
N/A Laryngoscope, 2023.
... Exciting studies examining the biological activities of MmuPV1 E6 and E7 are shedding light into how specific biochemical activities of the E6 and E7 proteins contribute to neoplastic disease induced by MmuPV1. MmuPV1 falls within the Pi genus, which contains other rodent PVs and is more closely related to the cutaneous βand γ-HPVs than the mucosal α-HPVs [181]. These similarities can be observed in the amino acid sequence, as MmuPV1 E6 and E7 share a number of amino acids with cutaneous HPVs only (Figures 1 and 2). ...
Human papillomaviruses (HPVs) cause a substantial amount of human disease from benign disease such as warts to malignant cancers including cervical carcinoma, head and neck cancer, and non-melanoma skin cancer. Our ability to model HPV-induced malignant disease has been impeded by species specific barriers and pre-clinical animal models have been challenging to develop. The recent discovery of a murine papillomavirus, MmuPV1, that infects laboratory mice and causes the same range of malignancies caused by HPVs provides the papillomavirus field the opportunity to test mechanistic hypotheses in a genetically manipulatable laboratory animal species in the context of natural infections. The E6 and E7 proteins encoded by high-risk HPVs, which are the HPV genotypes associated with human cancers, are multifunctional proteins that contribute to HPV-induced cancers in multiple ways. In this review, we describe the known activities of the MmuPV1-encoded E6 and E7 proteins and how those activities relate to the activities of HPV E6 and E7 oncoproteins encoded by mucosal and cutaneous high-risk HPV genotypes.
... In the time point study, the virus was incubated with the cells at 4°C for 1 h. Cells were washed 1Â with medium, and then 10 mg/mL MAb (MPV.A4, H18.J4, or H11.B2) was added to cells at different time points (1,2,4,6,8,12,24, and 30 h). The cells were incubated at 37°C for 3 additional days after the initial virus binding step and harvested with TRIzol reagent (Life Technologies). ...
... 38 cells was inhibited by MPV.A4 in a dose-and time-dependent manner (data not shown). In parallel with the in vivo studies, we conducted a time course neutralization experiment in K-38 cells to determine viral entry time and to test MPV.A4 neutralization at different time points post-viral inoculation(10,12,14,16,18, 110, 112, 124, and 130 h). This experiment was repeated several times for each time point. ...
This is the first study testing a single monoclonal neutralizing antibody (MPV.A4) by passive immunization against papillomavirus infections at both cutaneous and mucosal sites in the same host in the mouse papillomavirus model. We demonstrated that MPV.A4 administered before viral inoculation can protect both male and female athymic mice against MmuPV1 infections at cutaneous and mucosal sites.
... To our knowledge, the effect of MmuPV1 on cell junctions has not been previously explored. MmuPV1 E6 contains a putative PDZ-binding motif, but not in the extreme carboxy-terminus like high-risk HPV E6 proteins [84]. A straightforward decrease in ZO-1 may not be expected in either RRP or in MmuPV1-induced disease. ...
... Since immunodeficiency in NSG mice includes a lack of T cells and defective Langerhans cells at baseline, another mouse strain is required to understand interactions among keratins, cell adhesion molecules, and the immune response to MmuPV1 in the larynx and to generate a model that parallels human immune response to low-risk HPVs in RRP. Immunocompromised mouse strains are highly vulnerable to MmuPV1, but certain immunocompetent strains also develop infection and disease in various tissues [84,110,111]. This warrants investigation in the larynx. ...
Laryngeal infection with low-risk human papillomaviruses can cause recurrent respiratory papillomatosis (RRP), a disease with severe effects on vocal fold epithelium resulting in impaired voice function and communication. RRP research has been stymied by limited preclinical models. We recently reported a murine model of laryngeal MmuPV1 infection and disease in immunodeficient mice. In the current study, we compare quantitative and qualitative measures of epithelial proliferation, apoptosis, differentiation, and barrier between mice with MmuPV1-induced disease of the larynx and surrounding tissues and equal numbers of uninfected controls. Findings supported our hypothesis that laryngeal MmuPV1 infection recapitulates many features of RRP. Like RRP, MmuPV1 increased proliferation in infected vocal fold epithelium, expanded the basal compartment of cells, decreased differentiated cells, and altered cell–cell junctions and basement membrane. Effects of MmuPV1 on apoptosis were equivocal, as with RRP. Barrier markers resembled human neoplastic disease in severe MmuPV1-induced disease. We conclude that MmuPV1 infection of the mouse larynx provides a useful, if imperfect, preclinical model for RRP that will facilitate further study and treatment development for this intractable and devastating disease.
... The morbidity of RRP is exceedingly high due to the recurrent nature of the disease and a lack of satisfactory treatment options. RRP symptom management is limited to repeated surgical procedures to infect both cutaneous and mucosal epithelium and cause benign papilloma and cancer in many tissues [48][49][50]. MmuPV1 has been used to create novel preclinical models of HPV-associated mucosal disease in the cervix [51], anus [52], and head and neck [53][54][55]. Epithelial injury is typically performed in experimental MmuPV1 infection models, particularly in the skin [56]. ...
... The lack of an immune response to MmuPV1 could have resulted in the severe disease phenotypes observed in our study. We hypothesize that extending our work to immunocompetent mice will produce benign disease phenotypes, since MmuPV1 is capable of causing benign papillomas in addition to cancers [48][49][50]. Hypotheses for tissue-specific mechanisms underlying the laryngeal vulnerability to papillomaviruses warrant further study in immunocompetent mice. We expect some immunocompetent mice to clear the virus quickly and some to develop persistent disease, as shown in other tissues [48][49][50]119]. ...
... Hypotheses for tissue-specific mechanisms underlying the laryngeal vulnerability to papillomaviruses warrant further study in immunocompetent mice. We expect some immunocompetent mice to clear the virus quickly and some to develop persistent disease, as shown in other tissues [48][49][50]119]. Once we identify immunocompetent mice that can sustain laryngeal disease induced by MmuPV1, tissue-specific mechanisms can be explored. ...
Recurrent respiratory papillomatosis (RRP), caused by laryngeal infection with low-risk human papillomaviruses, has devastating effects on vocal communication and quality of life. Factors in RRP onset, other than viral presence in the airway, are poorly understood. RRP research has been stalled by limited preclinical models. The only known papillomavirus able to infect laboratory mice, Mus musculus papillomavirus (MmuPV1), induces disease in a variety of tissues. We hypothesized that MmuPV1 could infect the larynx as a foundation for a preclinical model of RRP. We further hypothesized that epithelial injury would enhance the ability of MmuPV1 to cause laryngeal disease, because injury is a potential factor in RRP and promotes MmuPV1 infection in other tissues. In this report, we infected larynges of NOD scid gamma mice with MmuPV1 with and without vocal fold abrasion and measured infection and disease pathogenesis over 12 weeks. Laryngeal disease incidence and severity increased earlier in mice that underwent injury in addition to infection. However, laryngeal disease emerged in all infected mice by week 12, with or without injury. Secondary laryngeal infections and disease arose in nude mice after MmuPV1 skin infections, confirming that experimentally induced injury is dispensable for laryngeal MmuPV1 infection and disease in immunocompromised mice. Unlike RRP, lesions were relatively flat dysplasias and they could progress to cancer. Similar to RRP, MmuPV1 transcript was detected in all laryngeal disease and in clinically normal larynges. MmuPV1 capsid protein was largely absent from the larynx, but productive infection arose in a case of squamous metaplasia at the level of the cricoid cartilage. Similar to RRP, disease spread beyond the larynx to the trachea and bronchi. This first report of laryngeal MmuPV1 infection provides a foundation for a preclinical model of RRP.
... Studying the mechanisms of viral pathogenesis of HPVs has been made possible by using several naturally occurring preclinical models (including cow, horse, dog, and rabbit) [15,16]. The mouse papillomavirus (MmuPV1) model provides a promising opportunity to study anogenital infection, as advanced diseases such as cancers have been reported in infected mice at the lower genital tract [17][18][19][20][21][22][23]. Our previous study also demonstrated that viral titers fluctuated during the mouse estrus cycle suggesting that changes in the hormone level may play a role in viral persistence [20]. ...
Contraceptives such as Depo-medroxyprogesterone (DMPA) are used by an estimated 34 million women worldwide. DMPA has been associated with increased risk of several viral infections including Herpes simplex virus-2 (HSV-2) and Human immunodeficiency virus (HIV). In the current study, we used the mouse papillomavirus (MmuPV1) anogenital infection model to test two hypotheses: (1) contraceptives such as DMPA increase the susceptibility of the anogenital tract to viral infection and (2) long-term contraceptive administration induces more advanced disease at the anogenital tract. DMPA treatments of both athymic nude mice and heterozygous NU/J (Foxn1nu/+) but ovariectomized mice led to a significantly increased viral load at the anogenital tract, suggesting that endogenous sex hormones were involved in increased viral susceptibility by DMPA treatment. Consistent with previous reports, DMPA treatment suppressed host anti-viral activities at the lower genital tract. To test the impact of long-term contraceptive treatment on the MmuPV1-infected lower genital tract, we included two other treatments in addition to DMPA: 17β-estradiol and a non-hormone based contraceptive Cilostazol (CLZ, Pletal). Viral infections were monitored monthly up to nine months post infection by qPCR. The infected vaginal and anal tissues were harvested and further examined by histological, virological, and immunological analyses. Surprisingly, we did not detect a significantly higher grade of histology in animals in the long-term DMPA and 17β-estradiol treated groups when compared to the control groups in the athymic mice we tested. Therefore, although DMPA promotes initial papillomavirus infections in the lower genital tract, the chronic administration of DMPA does not promote cancer development in the infected tissues in our mouse model.
... The Mastomys models have been used to study viral persistence [181], cutaneous tumorigenesis [182], the role of environmental factors like UV in papillomavirus-associated cutaneous disease and 'hit-and-run' oncogenesis [183], and other key aspects of papillomavirus pathogenesis [184]. There are several reviews that provide further information on preclinical rodent papillomavirus models and their contributions to our understanding of virus-host interactions and pathogenesis of papillomaviruses [136,137,185]. ...
... Notably, MmuPV1 exhibits expanded tropism in mice and causes disease in both cutaneous [189][190][191][192][193][194] and mucosal [138,189,[195][196][197][198][199][200][201] epithelia of immunodeficient and immunocompetent mice. This feature has facilitated the establishment of MmuPV1 infection-based models in all anatomical sites infected by HPVs in humans and these models are being used to study several aspects of pathogenesis and disease [reviewed in 138,185,202]. ...
Human tumor viruses cause various human cancers that account for at least 15% of the global cancer burden. Among the currently identified human tumor viruses, two are small DNA tumor viruses: human papillomaviruses (HPVs) and Merkel cell polyomavirus (MCPyV). The study of small DNA tumor viruses (adenoviruses, polyomaviruses, and papillomaviruses) has facilitated several significant biological discoveries and established some of the first animal models of virus-associated cancers. The development and use of preclinical in vivo models to study HPVs and MCPyV and their role in human cancer is the focus of this review. Important considerations in the design of animal models of small DNA tumor virus infection and disease, including host range, cell tropism, choice of virus isolates, and the ability to recapitulate human disease, are presented. The types of infection-based and transgenic model strategies that are used to study HPVs and MCPyV, including their strengths and limitations, are also discussed. An overview of the current models that exist to study HPV and MCPyV infection and neoplastic disease are highlighted. These comparative models provide valuable platforms to study various aspects of virus-associated human disease and will continue to expand knowledge of human tumor viruses and their relationship with their hosts.
... In support of the "hit and runs" mutagenesis hypothesis, deletion of E6/E7 after these lesions form did not affect cancer growth [29]. Rodent papillomaviruses resembling beta HPV were used to aid the study of cutaneous HPV biology in vivo [62][63][64][65]. Mastomys natalensis papilloma virus (MnPV) promotes cSCC in immunodeficient rats following UVB exposure [57]. ...
Beta human papillomavirus (beta HPV) infections are common in adults. Certain types of beta HPVs are associated with nonmelanoma skin cancer (NMSC) in immunocompromised individuals. However, whether beta HPV infections promote NMSC in the immunocompetent population is unclear. They have been hypothesized to increase genomic instability stemming from ultraviolet light exposure by disrupting DNA damage responses. Implicit in this hypothesis is that the virus encodes one or more proteins that impair DNA repair signaling. Fluorescence-based reporters, next-generation sequencing, and animal models have been used to test this primarily in cells expressing beta HPV E6/E7. Of the two, beta HPV E6 appears to have the greatest ability to increase UV mutagenesis, by attenuating two major double-strand break (DSB) repair pathways, homologous recombination, and non-homologous end-joining. Here, we review this dysregulation of DSB repair and emerging approaches that can be used to further these efforts.
... MmuPV1 E6 appeared to inhibit contact inhibition, increase growth postconfluence, resulting in higher saturation density, and delay keratinocyte differentiation (Fig. 6). This is similar to phenotypes observed in our recently published article, which showed exogenous expression of low-risk HPV11 E6, but not E7, afforded a growth advantage and differentiation delay to keratinocytes postconfluence (38), suggesting there may be similar mechanisms between mouse papillomavirus and low-risk HPV types, despite their relatively distant relationship (39). In the competition assay, which allows us to investigate the growth advantages of certain types of cells in mixed-cell populations in 3D by isolating discrete layers of cells within the monolayer culture, keratinocytes expressing MmuPV1 E6 demonstrated a clear phenotype of persistence in the "lower" layer of cells when cultured with control keratinocytes, whereas expression of MmuPV1 E7 did not (Fig. 7). ...
Papillomaviruses exclusively infect stratified epithelial tissues and cause chronic infections. To achieve this, infected cells must remain in the epithelial basal layer alongside their uninfected neighbours for years or even decades. To examine how papillomaviruses achieve this, we used the in vivo MmuPV1 model of lesion formation and persistence. During early lesion formation, an increased cell density in the basal layer, as well as a delay in the infected cells commitment to differentiation was apparent in cells expressing MmuPV1 E6/E7 RNA. Using cell culture models, keratinocytes exogenously expressing MmuPV1 E6, but not E7, recapitulated this delay in differentiation post-confluence and also grew to a significantly higher density. Cell competition assays further showed that MmuPV1 E6 expression led to a preferential persistence of the cell in the first layer, with control cells accumulating almost exclusively in the second layer. Interestingly, the disruption of MmuPV1 E6 binding to MAML1 protein abrogated these phenotypes. This suggests that the interaction between MAML1 and E6 is necessary for the lower (basal) layer persistence of MmuPV1 E6 expressing cells. Our results indicate a role for E6 in lesion establishment by facilitating the persistence of infected cells in the epithelial basal layer; a mechanism that is most likely shared by other papillomavirus types. Interruption of this interaction is predicted to impede persistent papillomavirus infection and consequently provides a novel treatment target.
Importance
Persistent infection with high-risk HPV types can lead to development of HPV-associated cancers, and persistent low-risk HPV infection causes problematic diseases, such as recurrent respiratory papillomatosis. The management and treatment of these conditions poses a considerable economic burden. Maintaining a reservoir of infected cells in the basal layer of the epithelium is critical for the persistence of infection in the host, and our studies using the mouse papillomavirus model suggest that E6 gene expression leads to the preferential persistence of epithelial cells in the lower layers during stratification. The E6 interaction with MAML1, a component of the Notch pathway, is required for this phenotype, and is linked to E6 effects on cell density and differentiation. These observations are likely to reflect a common E6 role that is preserved amongst papillomaviruses, and provide us with a novel therapeutic target for the treatment of recalcitrant lesions.
... Also, UV radiation can reactivate dormant viruses in rodents (Garssen et al., 1995;El-Ghorr and Norval, 1996;Norval and El-Ghorr, 1996;Goade et al., 2001;Norval, 2006;Viarisio et al., 2011). Epidemiological data on papillomaviruses and herpesviruses suggest the same assumption holds for humans (Chen et al., 2008;Hampras et al., 2014;Uberoi and Lambert, 2017). The mechanism of this reactivation is related to how UV radiation suppresses the immune system (Norval and Halliday, 2011;Schwarz and Schwarz, 2011;Ullrich and Byrne, 2012) by activation of regulatory T cells (thymus cells, a type of lymphocyte) that produce immunosuppressive signals and thus inhibit the immune system (Rana et al., 2008). ...
Viruses constitute a significant part of the human microbiome, so wherever humans go, viruses are brought with them, even on space missions. In this mini review, we focus on the International Space Station (ISS) as the only current human habitat in space that has a diverse range of viral genera that infect microorganisms from bacteria to eukaryotes. Thus, we have reviewed the literature on the physical conditions of space habitats that have an impact on both virus transmissibility and interaction with their host, which include UV radiation, ionizing radiation, humidity, and microgravity. Also, we briefly comment on the practices used on space missions that reduce virus spread, that is, use of antimicrobial surfaces, spacecraft sterilization practices, and air filtration. Finally, we turn our attention to the health threats that viruses pose to space travel. Overall, even though efforts are taken to ensure safe conditions during human space travel, for example, preflight quarantines of astronauts, we reflect on the potential risks humans might be exposed to and how those risks might be aggravated in extraterrestrial habitats.
