IntroductionHuman polyomaviruses (HPyVs) cause persistent/latent infections in a large fraction of the population. HPyV infections may cause severe diseases in immunocompromised patients. Malawi polyomavirus (MWPyV) is the 10th discovered human polyomavirus (HPyV 10). MWPyV was found in stool samples of healthy children. So far, the few investigations carried out on HPyV 10 did not find an association with human disease.MethodsIn this study, to verify the putative association between MWPyV and human diseases, MWPyV seroprevalence was investigated in patients affected by i) lymphoproliferative disorders (LPDs) and ii) immune system disorders, i.e., autoimmune diseases (ADs), and in iii) healthy subjects. An indirect ELISA, employing virus-like particles (VLPs) to detect serum IgG antibodies against MWPyV/HPyV 10, was carried out. The study also revealed the prevalence of another polyomavirus, Merkel cell polyomavirus (MCPyV).ResultsSera from patients with distinct autoimmune diseases (n = 44; mean age 20 years) had a prevalence of MWPyV antibodies of 68%, while in patients with lymphoproliferative disorders (n = 15; mean age 14 years), subjected to bone marrow transplantation, the prevalence was 47%. In healthy subjects (n = 66; mean age 13 years), the prevalence of MWPyV antibodies was 67%. Our immunological investigation indicates that MWPyV/HPyV 10 seroconversion occurs early in life and MWPyV/HPyV 10 appears to be another polyomavirus ubiquitous in the human population. A significantly lower MWPyV antibody reactivity together with a lower immunological profile was detected in the sera of LPD patients compared with HS2 (*p < 0.05) (Fisher’s exact test). LPD and AD patients have a similar MCPyV seroprevalence compared with healthy subjects.DiscussionMWPyV seroprevalence indicates that this HPyV is not associated with lymphoproliferative and autoimmune diseases. However, the ability to produce high levels of antibodies against MWPyV appears to be impaired in patients with lymphoproliferative disorders. Immunological investigations indicate that MWPyV seroconversion occurs early in life. MCPyV appears to be a ubiquitous polyomavirus, like other HPyVs, in the human population.

Vaccines against hepatitis B virus (HBV) and human papillomaviruses (HPV) are two safe and highly effective vaccines that were developed at the end of the 20th century and can prevent human cancer. HBV vaccine prevents liver cancer, and HPV prevents cervical and other HPV-related cancers. Starting with the immunogen identification, 15 years were necessary to reach the industrial production of HBV vaccine, and 20 years, for the HPV vaccines. However, while HBV vaccines have been commercially available for over 40 years and are used in most countries, there are still significant challenges to achieve universal childhood immunization against hepatitis B. Similarly, HPV vaccines have been commercially available for 17 years, and yet, countries with higher cervical cancer still have the lowest HPV vaccination rates. We describe the development of HBV and HPV vaccines and discuss the challenges to reaching equitable access to these vaccines in Latin America.

RésuméLes papillomavirus humains responsables du cancer du col de l’utérus ont été identifiés au début des années 1980. Le rôle causal de certains de ces virus a été confirmé par plusieurs études épidémiologiques, et au début des années 1990 des vaccins constitués de la protéine majeure de la capside virale ont montré leur efficacité dans des modèles animaux de papillomavirus. Ces résultats ont rendu possible le développement de vaccins contre le cancer du col de l’utérus et d’autres cancers induits par les papillomavirus génitaux.Cette revue présente les données récentes concernant l’efficacité des vaccins contre les papillomavirus. Les premiers résultats obtenus lors de grandes études randomisées ont conduit, à partir de 2006, à la commercialisation de quatre vaccins. Depuis, de nombreuses études ont confirmé la très grande innocuité et la remarquable efficacité de ces vaccins contre les lésions pré-cancéreuses associées aux différents cancers induits par les papillomavirus. Même si les vaccins contre les papillomavirus se sont montrés très efficaces et d’une grande sûreté, l’extension de la vaccination contre les papillomavirus se heurte à l’hésitation de la population et à la désinformation concernant son innocuité conduisant dans certains pays, dont la France, à une couverture vaccinale très insuffisante. Plus récemment, l’efficacité de la vaccination contre les papillomavirus génitaux dans la prévention du cancer du col de l’utérus a été démontrée en Suède et au Royaume-Uni.

Trichodysplasia spinulosa polyomavirus (TSPyV) has recently been identified as the probable etiological agent of trichodysplasia spinulosa, a rare and severe proliferative skin disorder observed in immunocompromized patients, especially children (Rouanet et al., 2016Rouanet J. Aubin F. Gaboriaud P. Berthon P. Feltkamp M.C. Bessenay L. et al.Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients.Br J Dermatol. 2016; 174: 629-632Crossref PubMed Scopus (15) Google Scholar, van der Meijden et al., 2010van der Meijden E. Janssens R.W. Lauber C. Bouwes Bavinck J.N. Gorbalenya A.E. Feltkamp M.C. Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient.PLoS Pathogens. 2010; 6: e1001024Crossref PubMed Scopus (375) Google Scholar). Recent serological studies have indicated that TSPyV infection is common and that TSPyV seroprevalence increases rapidly with age from childhood to reach approximately 70–90% in adults in blood donors and in populations of hospitalized patients in Europe, Australia, and Japan (Chen et al., 2011Chen T. Mattila P.S. Jartti T. Ruuskanen O. Soderlund-Venermo M. Hedman K. Seroepidemiology of the newly found trichodysplasia spinulosa-associated polyomavirus.J Infect Dis. 2011; 204: 1523-1526Crossref PubMed Scopus (61) Google Scholar, Fukumoto et al., 2015Fukumoto H. Li T.C. Kataoka M. Hasegawa H. Wakita T. Saeki H. et al.Seroprevalence of trichodysplasia spinulosa-associated polyomavirus in Japan.J Clin Virol. 2015; 65: 76-82Crossref PubMed Scopus (16) Google Scholar, Nicol et al., 2013Nicol J.T. Robinot R. Carpentier A. Carandina G. Mazzoni E. Tognon M. et al.Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.Clin Vaccine Immunol. 2013; 20: 363-368Crossref PubMed Scopus (124) Google Scholar, Sroller et al., 2016Sroller V. Hamsikova E. Ludvikova V. Musil J. Nemeckova S. Salakova M. Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors.J Med Virol. 2016; 88: 1254-1261Crossref PubMed Scopus (31) Google Scholar, van der Meijden et al., 2013van der Meijden E. Bialasiewicz S. Rockett R.J. Tozer S.J. Sloots T.P. Feltkamp M.C. Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin.PLoS One. 2013; 8: e81078Crossref PubMed Scopus (84) Google Scholar). However, seroprevalence data are lacking for other populations, and the routes by which this virus is transmitted and acquired remain unknown. This work aims to obtain new insight into the modes of distribution and acquisition of TSPyV from family-based epidemiological analyses in African populations. This study was carried out on two populations from Cameroon, Central Africa, in which we previously reported epidemiological studies searching for intrafamilial transmission of human herpes virus-8 and Merkel cell polyomavirus (MCPyV) (Martel-Jantin et al., 2013Martel-Jantin C. Pedergnana V. Nicol J.T. Leblond V. Tregouet D.A. Tortevoye P. et al.Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings.J Clin Virol. 2013; 58: 288-291Crossref PubMed Scopus (73) Google Scholar, Plancoulaine et al., 2000Plancoulaine S. Abel L. van Beveren M. Tregouet D.A. Joubert M. Tortevoye P. et al.Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.Lancet. 2000; 356: 1062-1065Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). The first population, from Yaoundé, consisted mostly of children. The second consisted of villagers living in an isolated rural area of Southern Cameroon, Ntem, for which familial relationships with full pedigrees were established. This survey was performed with authorization from the local authorities. Each participant was provided with information about the study, and written informed consent was obtained from adults or from the parents of minors. The study received ethical clearance in Cameroon from the National Ethics Committee and in France from the Comité de Protection des Personnes and the Commission Nationale de l'Informatique et des Libertés. Specific antibodies against TSPyV were tested by ELISA, in which anti-VP1 antibodies were detected with TSPyV-like viral particles generated in insect cells, as previously described (Nicol et al., 2013Nicol J.T. Robinot R. Carpentier A. Carandina G. Mazzoni E. Tognon M. et al.Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.Clin Vaccine Immunol. 2013; 20: 363-368Crossref PubMed Scopus (124) Google Scholar). These assays are type specific because no evidence of cross-reactivity has been reported between other polyomaviruses and TSPyV (Nicol et al., 2013Nicol J.T. Robinot R. Carpentier A. Carandina G. Mazzoni E. Tognon M. et al.Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.Clin Vaccine Immunol. 2013; 20: 363-368Crossref PubMed Scopus (124) Google Scholar). Plasma samples were tested at a 1:100 dilution. In the first population, which comprised 450 individuals (sex ratio = 0.96, 312 children), the overall seroprevalence of antibodies against TSPyV-VP1 was 69.8%, with no significant difference (P > 0.05) between female (73.8%) and male (65.6%) participants. We further investigated the age at which the virus was acquired by focusing on young children. Seroprevalence was high, at about 70%, from birth until the age of 2 months (Figure 1a), similar to what is observed in women of childbearing age (∼80%). Seroprevalence then first decreased, reaching 30–40% at 13–36 months of age and then rapidly and steadily increased from 3 years, to reach about 70% in children at age 11 years. This pattern of seroprevalence is consistent with the presence of maternal antibodies in very young children. These maternal antibodies then progressively disappear, and infection is rapidly acquired in most children, beginning from the age of 1 to 3 years. In our second analysis, we specifically studied a familial sample of 527 individuals (sex ratio = 1.00) ages 1 to 92 years (median age = 18 years) from an isolated village, Ntem. The overall TSPyV seroprevalence was 84%, with no significant difference (P > 0.05) between female (85.2%) and male (83.7%) participants. Seroprevalence increased rapidly with age, from approximately 40% in children younger than 2 years to 85% in adults older than 20 years (Figure 1a). Various age-coding schemes were tested to account for this highly significant age effect, and the best fit was obtained for a model in which the logarithm of age was considered as a quantitative variable (P < 5.5 × 10–6). The 527 subjects were clustered into 65 families, each with 2–25 members, and the second step of the analysis was to estimate the familial aggregation of serological status for TSPyV (infected or noninfected). Although the correlation between spouses (i.e., the father and mother of the family) could be estimated, it was not significant, because almost all adults were seropositive. We estimated the following three familial correlations: father-child, mother-child and child-child. Figure 1b shows the results of the familial odds ratio (OR) estimations with the second-order estimating equations approach, adjusted for age, as previously described (Plancoulaine et al., 2000Plancoulaine S. Abel L. van Beveren M. Tregouet D.A. Joubert M. Tortevoye P. et al.Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.Lancet. 2000; 356: 1062-1065Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). A highly significant correlation was found between mother and children (OR = 7.28, 95% confidence interval [CI] = 2.02–26.25, P = 0.002), and a similar trend, although not nominally significant, was observed between father and children (OR = 3.19, 95% CI = 0.97–10.51, P = 0.06). We further investigated the mother-children correlation by testing if the risk of infection in children may depend on TSPyV antibody levels in infected mothers. No correlation between the TSPyV antibody levels of infected mothers (as measured by the ELISA optical density) and the proportion of seropositive children was found (see Supplementary Table S1 online). Finally, TSPyV serological status was significantly correlated (P = 0.01) between siblings, with an OR of 1.95 (95% CI = 1.16–3.27). Furthermore, the OR was higher for pairs in which the two siblings were closer in age (age difference of less than 7 years, to give a balanced number of child-child pairs in each subgroup), in which it reached 2.44 (95% CI = 1.16–5.82, P = 0.02), than for sibling pairs with an age difference of 7 years or greater (OR = 1.28, 95% CI = 0.45–3.37, P > 0.05). This study clearly shows the high seroprevalence of antibodies directed against TSPyV in children and adults living in Central Africa. This confirms and extends to Africa previous findings of a high level of serological evidence of TSPyV exposure in young children living in Europe, Australia, and Japan (Chen et al., 2011Chen T. Mattila P.S. Jartti T. Ruuskanen O. Soderlund-Venermo M. Hedman K. Seroepidemiology of the newly found trichodysplasia spinulosa-associated polyomavirus.J Infect Dis. 2011; 204: 1523-1526Crossref PubMed Scopus (61) Google Scholar, Fukumoto et al., 2015Fukumoto H. Li T.C. Kataoka M. Hasegawa H. Wakita T. Saeki H. et al.Seroprevalence of trichodysplasia spinulosa-associated polyomavirus in Japan.J Clin Virol. 2015; 65: 76-82Crossref PubMed Scopus (16) Google Scholar, Nicol et al., 2013Nicol J.T. Robinot R. Carpentier A. Carandina G. Mazzoni E. Tognon M. et al.Age-specific seroprevalences of Merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.Clin Vaccine Immunol. 2013; 20: 363-368Crossref PubMed Scopus (124) Google Scholar, Sroller et al., 2016Sroller V. Hamsikova E. Ludvikova V. Musil J. Nemeckova S. Salakova M. Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors.J Med Virol. 2016; 88: 1254-1261Crossref PubMed Scopus (31) Google Scholar, van der Meijden et al., 2013van der Meijden E. Bialasiewicz S. Rockett R.J. Tozer S.J. Sloots T.P. Feltkamp M.C. Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin.PLoS One. 2013; 8: e81078Crossref PubMed Scopus (84) Google Scholar). Moreover, our epidemiological data indicate that most primary TSPyV infections (at least 50 to 70% of these infections) occurred during early childhood, after the disappearance of specific maternal antibodies. This indicates that mother-fetus transmission is not a major route of TSPyV transmission. Lastly, the correlations in serological status for TSPyV infection observed within families strongly suggest that TSPyV is transmitted from parents to children, especially from the mother, and also between siblings (in particular when they are close in age). In addition, the antibody levels in infected mothers did not influence the risk of infection in their children. This pattern is quite similar to that found in this population for human herpes virus-8 and for MCPyV, which are thought to be transmitted through close contacts involving saliva and skin, respectively (Martel-Jantin et al., 2013Martel-Jantin C. Pedergnana V. Nicol J.T. Leblond V. Tregouet D.A. Tortevoye P. et al.Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings.J Clin Virol. 2013; 58: 288-291Crossref PubMed Scopus (73) Google Scholar, Plancoulaine et al., 2000Plancoulaine S. Abel L. van Beveren M. Tregouet D.A. Joubert M. Tortevoye P. et al.Human herpesvirus 8 transmission from mother to child and between siblings in an endemic population.Lancet. 2000; 356: 1062-1065Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). To date, TSPyV has been detected on the skin and in nasopharynx, tonsils, stools, cerebrospinal fluid, and urine samples (Rockett et al., 2013Rockett R.J. Sloots T.P. Bowes S. O'Neill N. Ye S. Robson J. et al.Detection of novel polyomaviruses, TSPyV, HPyV6, HPyV7, HPyV9 and MWPyV in feces, urine, blood, respiratory swabs and cerebrospinal fluid.PLoS One. 2013; 8: e62764Crossref PubMed Scopus (47) Google Scholar, Sadeghi et al., 2014Sadeghi M. Aaltonen L.M. Hedman L. Chen T. Soderlund-Venermo M. Hedman K. Detection of TS polyomavirus DNA in tonsillar tissues of children and adults: evidence for site of viral latency.J Clin Virol. 2014; 59: 55-58Crossref PubMed Scopus (33) Google Scholar, Urbano et al., 2016Urbano P.R. Nali L.H. Bicalho C.S. Pierrotti L.C. David-Neto E. Pannuti C.S. et al.New findings about trichodysplasia spinulosa-associated polyomavirus (TSPyV)—novel qPCR detects TSPyV-DNA in blood samples.Diagn Microbiol Infect Dis. 2016; 84: 123-124Crossref PubMed Scopus (12) Google Scholar). This suggests that these sites may act as reservoirs and could play a role in viral dissemination. Overall, our analyses strongly suggest that TSPyV can be transmitted within families through close interpersonal contacts, particularly between mother to child and between young siblings. The authors state no conflict of interest. This work was supported by the French Government's Investissement d'Avenir program, Laboratoire d'Excellence "Integrative Biology of Emerging Infectious Diseases" (grant no. ANR-10-LABX-62-IBEID), by the Institut Pasteur in Paris. CMJ was supported by the Ministère de l'Enseignement Supérieur et de la Recherche of France and Paris Diderot University and JN was supported by a grant from the Région Centre, France. We thank the Institut de Recherche pour le Développement and the Centre Pasteur du Cameroun for their collaboration in the field work carried out in Cameroon. Download .pdf (.06 MB) Help with pdf files Supplementary Table S1

Le Polyomavirus à cellules de Merkel (MCPyV) est reconnu depuis 2012 par l’IARC comme l’agent étiologique du carcinome à cellules de Merkel chez l’Homme. Cependant, les mécanismes conduisant à l’infection puis à l’oncogenèse viro-induite sont peu connus. Nos travaux ont pour objectifs d’identifier les partenaires cellulaires des oncoprotéines (antigènes T et t) du MCPyV afin de caractériser son virhostome (virus-host interactome). L’identification des interactions entre les partenaires cellulaires et les protéines virales est réalisée par l’utilisation de la technologie du double hybride en levures puis validée à l’aide d’un test de complémentation en cellules de mammifère (HT-GPCA, High-Throughput Gaussia Princeps Complementation Assay). Grâce à ces deux techniques, nous avons mis en évidence diverses interactions entre l’oncogène sT (small T) et des protéines cellulaires impliquées notamment dans le cycle cellulaire ou encore de la voie NFκB. Par ailleurs, nous avons identifié une interaction entre cet antigène et la protéine phosphatase PP2A, connue pour son implication dans des voies de signalisation oncogéniques, ainsi qu’avec l’oncogène LT (Large T). L’effet biologique de ces interactions sur les voies de signalisation est en cours de caractérisation. Ces résultats pourront nous permettre de comprendre la biologie du virus et les étapes de l’oncogenèse viro-induite afin d’identifier de potentielles cibles thérapeutiques.

Background: Swine pasivirus (SPaV1) is a recently described enteric virus close to human parechoviruses and highly prevalent in pigs. Antibodies to Escherichia coli-expressed VP1 of SpaV1 have been found in a majority of humans in China.Objectives: The objectives were to estimate the antibody prevalence in a European country, to test if exposure to the virus was linked to pig products and if this exposure was a risk factor for the development of diabetes type 1.Study design: An ELISA test was developed and used to screen 842 healthy subjects with known exposure to pig products, 39 patients with diabetes type 1 and 20 controls.Results: We identified a high seroprevalence (15.6%) reacting to VP1 of SPaV1 among healthy human subjects. Analysis of risk factors argues against cross-species transmission from pigs as the source of infection. Data also indicate that the presence of SPaV1 VP1-binding antibodies is not associated with diabetes type 1 in humans.Conclusion: Our results suggest that the seroreactivity frequently found in humans against SpaV1 is due to cross-reactivity with related antigen, perhaps a picornavirus, and that SpaV1 is not a zoonotic virus. (C) 2015 Elsevier B.V. All rights reserved.

Background/Aims: Merkel cell carcinoma (MCC) is a rare high-grade neuroendocrine tumour of the skin. It has been speculated that MCCs express somatostatin receptors (SSTRs), but this has never been assessed in a large series of MCCs. The main aim of this study was to assess the expression of SSTR2A and SSTR5 in MCC tumours. The secondary aims were to assess whether expression of SSTR was associated with the Ki67 proliferative index, Merkel cell polyomavirus (MCPyV) status, clinical characteristics and outcome. Methods: Clinical data and tumours were collected from an ongoing cohort of French patients with MCC. Immunohistochemistry was performed with anti-SSTR2A and anti-SSTR5 monoclonal antibodies, and tumours were classified into 3 groups: ‘no expression', ‘low expression' and ‘moderate expression' using an SSTR staining score. Results: SSTR expression was assessed for 105 MCC tissue samples from 98 patients, and clinical characteristics were available for 87 of them. SSTR expression was consistent between the primary skin tumour and the corresponding metastases for SSTR2A and SSTR5 in 3/7 and 6/7 cases, respectively. SSTR2A and SSTR5 were expressed in 58 cases (59.2%) and in 44 cases (44.9%), respectively. Overall, at least one SSTR was expressed in 75 tumours (76.5%). SSTR expression was not associated with clinical characteristics, Ki67 proliferative index, recurrence-free survival or MCC-specific survival. Expression of SSTR2A was associated with MCPyV status in MCC tumours but not SSTR5. Conclusion: SSTRs were expressed in a high proportion of MCCs, although expression was heterogeneous between tumours and was not associated with disease severity.

Merkel cell polyomavirus (MCPyV) is the first polyomavirus clearly associated with a human cancer, i.e. the Merkel cell carcinoma (MCC). Polyomaviruses are small naked DNA viruses that induce a robust polyclonal antibody response against the major capsid protein (VP1). However, the polyomavirus VP1 capsid protein epitopes have not been identified to date. The aim of this study was to identify the neutralizing epitopes of the MCPyV capsid. For this goal, four VP1 mutants were generated by insertional mutagenesis in the BC, DE, EF and HI loops between amino acids 88-89, 150-151, 189-190, and 296-297, respectively. The reactivity of these mutants and wild-type VLPs was then investigated with anti-VP1 monoclonal antibodies and anti-MCPyV positive human sera. The findings together suggest that immunodominant conformational neutralizing epitopes are present at the surface of the MCPyV VLPs and are clustered within BC and EF loops.

ABSTRACT Merkel cell polyomavirus (MCPyV) is linked to a cutaneous cancer mainly occurring in Caucasians. DNA from skin swabs of 255 adults, originating from the 5 continents, were subjected to MCPyV PCRs. Phylogenetic analyses demonstrate the existence of 5 major geographically related MCPyV genotypes (Europe/North America, Africa [sub-Saharan], Oceania, South America, and Asia/Japan).

ABSTRACT The seroprevalence of the recently discovered human Malawi polyomavirus (MWPyV) was determined by virus-like particle-based enzyme-linked immunosorbent assay (ELISA) in age-stratified Italian subjects. The findings indicated that MWPyV infection occurs early in life, and seroprevalence was shown to reach 42% in adulthood.

Merkel cell carcinoma (MCC) is a rare and often aggressive cutaneous cancer with a poor prognosis. The incidence of this cancer increases with age, immunodeficiency and sun exposure. Merkel cell polyomavirus (MCPyV), a new human polyomavirus identified in 2008, is detected in the majority of the MCCs and there is a growing body of evidence that healthy human skin harbors resident or transient MCPyV. A causal link between MCPyV and MCC has been evidenced and this is the first polyomavirus to be clearly implicated as a causal agent underlying a human cancer, and MCPyV was recently classified as a 2A carcinogen. MCC is thus a rare tumor caused by a very common viral skin infection. The aim of this review is to provide a basic overview of the epidemiological, clinical, and pathological characteristics of MCC, to present the current knowledge on MCPyV polyomavirus and its causal association with MCC development, and to describe the therapeutic implications of this causal link.

Virus‐like particles (VLPs) of human papillomavirus (HPV) are used as a vaccine against HPV‐induced cancer, and recently we have shown that these VLPs are able to activate natural killer (NK) cells. Since NK cells collaborate with dendritic cells (DCs) to induce an immune response against viral infections and tumors, we studied the impact of this crosstalk in the context of HPV vaccination. NK cells in the presence of HPV‐VLPs enhanced DC‐maturation as shown by an upregulation of CD86 and HLA‐DR and an increased production of IL‐12p70, but not of the immunosuppressive cytokine IL‐10. This activation was bidirectional. Indeed, in the presence of HPV‐VLPs, DCs further activated NK cells by inducing the upregulation of cell surface activation markers (CD69 and HLA‐DR). The function of NK cells was also improved as shown by an increase in IFN‐γ secretion and cytotoxic activity against an HPV+ cell line. This crosstalk between NK cells and DCs needed CD40 interaction and IL‐12p70 secretion, whereas NKG2D was not implicated. Our results provide insight into how VLPs interact with innate immune cells and how NK cells and DCs play a role in the immune response induced by this vaccine agent.

HPV prophylactic vaccination based on VLPs was implemented 7 years ago and has now shown a high degree of efficiency to reduce HPV-induced lesions. Moreover, it was shown that HPV-derived virus-like particles or pseudovirions could be used as gene therapy vectors. As a consequence, characterization of the antigenic structure of HPV capsids is crucial for designing future HPV vaccines with better or broader efficacy and for the design of HPV-derived gene therapy vectors with reduced immunogenicity or vaccination escaping. In this study, we have generated 10 HPV16 FG loop L1 protein mutants and analyzed their ability to self-assemble into VLP, their immunogenicity, and their ability to transduce cells when used as pseudovirions. Most of the mutants had lost their ability to transduce cells at the exception of two chimeric HPV16/31 L1 protein FG loop mutants. Sera from mice immunized with HPV16 L1 wt VLPs very weakly neutralized pseudovirions derived from these two HPV16/31 L1 protein FG loop mutants. These findings suggest that only a few point substitutions within the FG loop are sufficient to generate a new serotype escaping vaccination. As a consequence, derived pseudovirions might be suitable as gene therapy vectors in vaccinated subjects.

Phylogenetic analyses based on the major capsid protein sequence indicate that Merkel cell polyomavirus (MCPyV) and chimpanzee polyomaviruses (PtvPyV1, PtvPyV2), and similarly Trichodysplasia spinulosa-associated polyomavirus (TSPyV) and the orangutan polyomavirus (OraPyV1) are closely related. The existence of cross-reactivity between these polyomaviruses was therefore investigated. The findings indicated serological identity between the two chimpanzee polyomaviruses investigated and a high level of cross-reactivity with Merkel cell polyomavirus. In contrast, cross-reactivity was not observed between TSPyV and OraPyV1. Furthermore, specific antibodies to chimpanzee polyomaviruses were detected in chimpanzee sera by pre-incubation of sera with the different antigens, but not in human sera.

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The Merkel cell polyomavirus (MCPyV), identified in humans in 2008, is associated with a relatively rare but aggressive neuroendocrine skin cancer, the Merkel cell carcinoma (MCC). MCC incidence is increasing due to the advancing age of the population, the increase in damaging sun exposure and in the number of immunocompromised individuals. MCPyV must be considered as the etiological agent of MCC and thus is the first example of a human oncogenic polyomavirus. MCPyV infection is common, and seroprevalence studies indicate that widespread exposure begins early in life. The majority of adults have anti-MCPyV antibodies and there is a growing body of evidence that healthy human skin harbors resident or transient MCPyV suggesting that MCPyV infection persists throughout life. However, the mode of transmission, the host cells, and the latency characteristics of this virus remain to be elucidated. In addition, it is still not clear whether MCPyV is associated with diseases or lesions other than Merkel cell carcinoma. The etiologic role of MCPyV in MCC opens up opportunities to improve the understanding of this cancer and to potentially improve its treatment.

Six new human polyomaviruses have been identified since 2008 (Merkel cell polyomavirus [MCPyV], human polyomavirus 6 [HPyV6], HPyV7, HPyV9, trichodysplasia spinulosa polyomavirus [TSPyV], and Malawi polyomavirus [MWPyV]). The presence of specific antibodies against MCPyV, HPyV6, HPyV7, HPyV9, and TSPyV in 828 Italian subjects aged 1 to 100 years was investigated by virus-like particle-based enzyme-linked immunosorbent assays (ELISAs). The findings indicate that all of these new polyomaviruses circulate widely in humans, with seroprevalences in adulthood ranging from 39.4% for HPyV9 to 87.1% for MCPyV, and that primary exposure is most intense in childhood, with the exception of HPyV7 and HPyV9, for which the sero-prevalence increased throughout life. The proportion of subjects with high antibody titers was found to increase with age for MCPyV and to decrease with age for TSPyV.