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1.  Isolation of Protein-Associated Circular DNA from Healthy Cattle Serum 
Genome Announcements  2014;2(4):e00846-14.
Three replication-competent single-stranded DNA molecules sharing nucleotide similarity to transmissible spongiform encephalopathy (TSE)-associated isolate Sphinx 2.36 were isolated from healthy bovine serum.
doi:10.1128/genomeA.00846-14
PMCID: PMC4148724  PMID: 25169856
2.  Isolation of Bacterial Plasmid-Related Replication-Associated Circular DNA from a Serum Sample of a Multiple Sclerosis Patient 
Genome Announcements  2014;2(4):e00847-14.
Psychrobacter species are considered to be opportunistic human pathogens. We report here the isolation of a circular DNA molecule, MSSI1.162, from a serum sample taken from a multiple sclerosis patient during relapse. This isolate is distantly related to known Psychrobacter species and their plasmids.
doi:10.1128/genomeA.00847-14
PMCID: PMC4148725  PMID: 25169857
3.  Mycovirus-Like DNA Virus Sequences from Cattle Serum and Human Brain and Serum Samples from Multiple Sclerosis Patients 
Genome Announcements  2014;2(4):e00848-14.
Myco-like viruses have been isolated from fungi, feces of various animals, and plant leaves. We report here the isolation of 3 complete genome sequences of gemycircularvirus-related viruses from healthy bovine serum and human brain and serum samples from patients with multiple sclerosis (MS). Their putative capsid proteins share similarity to Torque teno virus (TTV) open reading frame 1 (ORF1) proteins.
doi:10.1128/genomeA.00848-14
PMCID: PMC4148726  PMID: 25169858
4.  Novel Replication-Competent Circular DNA Molecules from Healthy Cattle Serum and Milk and Multiple Sclerosis-Affected Human Brain Tissue 
Genome Announcements  2014;2(4):e00849-14.
Epidemiological data point to the involvement of a cow milk factor in the etiology of multiple sclerosis (MS). Eleven circular DNA molecules closely related to transmissible spongiform encephalopathy (TSE)-associated isolate Sphinx 1.76 were isolated from healthy cattle serum, cow milk, and serum and brain tissue from MS patients.
doi:10.1128/genomeA.00849-14
PMCID: PMC4148727  PMID: 25169859
5.  A Human Torque Teno Virus Encodes a MicroRNA That Inhibits Interferon Signaling 
PLoS Pathogens  2013;9(12):e1003818.
Torque teno viruses (TTVs) are a group of viruses with small, circular DNA genomes. Members of this family are thought to ubiquitously infect humans, although causal disease associations are currently lacking. At present, there is no understanding of how infection with this diverse group of viruses is so prevalent. Using a combined computational and synthetic approach, we predict and identify miRNA-coding regions in diverse human TTVs and provide evidence for TTV miRNA production in vivo. The TTV miRNAs are transcribed by RNA polymerase II, processed by Drosha and Dicer, and are active in RISC. A TTV mutant defective for miRNA production replicates as well as wild type virus genome; demonstrating that the TTV miRNA is dispensable for genome replication in a cell culture model. We demonstrate that a recombinant TTV genome is capable of expressing an exogenous miRNA, indicating the potential utility of TTV as a small RNA vector. Gene expression profiling of host cells identifies N-myc (and STAT) interactor (NMI) as a target of a TTV miRNA. NMI transcripts are directly regulated through a binding site in the 3′UTR. SiRNA knockdown of NMI contributes to a decreased response to interferon signaling. Consistent with this, we show that a TTV miRNA mediates a decreased response to IFN and increased cellular proliferation in the presence of IFN. Thus, we add Annelloviridae to the growing list of virus families that encode miRNAs, and suggest that miRNA-mediated immune evasion can contribute to the pervasiveness associated with some of these viruses.
Author Summary
The torque teno viruses (TTVs) are a diverse group of viruses that ubiquitously infect humans and establish persistent infections. Despite their prevalence, TTVs lack concrete disease associations and remain among the most poorly characterized human viruses. Here we use computational and synthetic approaches to identify new noncoding miRNA genes in the TTVs. We demonstrate that TTVs utilize the host miRNA biogenesis machinery to produce biologically active miRNAs. To gain a functional understanding of the new TTV genes, we focus on a particular viral isolate and identify N-myc (and STAT) interactor (NMI) as a direct target. NMI is a known modulator of interferon and cytokine signaling. Similar to other viruses encoding miRNAs, the TTVs likely utilize miRNAs to promote persistence and immune evasion. Our study provides new insights into novel TTV gene products and the interactions of this virus with its host.
doi:10.1371/journal.ppat.1003818
PMCID: PMC3868544  PMID: 24367263
6.  Cutaneous Human Papillomaviruses Found in Sun-Exposed Skin: Beta-papillomavirus Species 2 Predominates in Squamous Cell Carcinoma 
The Journal of infectious diseases  2007;196(6):876-883.
Background
A spectrum of cutaneous human papillomaviruses (HPVs) is detectable in nonmelanoma skin cancers, as well as in healthy skin, but the significance that the presence of these types of HPV DNA has for the pathogenesis of skin cancer remains unclear.
Methods
We studied 349 nonimmunosuppressed patients with skin lesions (82 with squamous cell carcinomas, 126 with basal cell carcinomas, 49 with actinic keratoses, and 92 with benign lesions). After superficial skin had been removed by tape, paired biopsy samples—from the lesion and from healthy skin from the same patient—were tested for HPV DNA. Risk factors for HPV DNA were analyzed in multivariate models.
Results
Overall, 12% of healthy skin samples were positive for HPV DNA, compared with 26% of benign lesions, 22% of actinic keratoses, 18% of basal cell carcinomas, and 26% of squamous cell carcinomas. HPV DNA was associated with sites extensively exposed to the sun, both for the lesions (odds ratio [OR], 4.45 [95% confidence interval {CI}, 2.44–8.11]) and for the healthy skin samples (OR, 3.65 [95% CI 1.79–7.44]). HPV types of Beta-papillomavirus species 2 predominate in squamous cell carcinomas (OR, 4.40 [95% CI, 1.92–10.06]), whereas HPV types of Beta-papillomavirus species 1 are primarily found in benign lesions (OR, 3.47 [95% CI, 1.72–6.99]).
Conclusions
Cutaneous HPV types are primarily detected at sites extensively exposed to the sun. HPV types of Beta-papillomavirus species 2, but not of species 1, are associated with squamous cell carcinoma.
doi:10.1086/521031
PMCID: PMC3795387  PMID: 17703418
7.  The transcriptional regulator gene E2 of the Human Papillomavirus (HPV) 16 influences the radiosensitivity of cervical keratinocytes 
Background
Clinical studies have demonstrated that HPV induced tumors constitute a specific subclass of cancer with a better response to radiation treatment. The purpose of this study was to investigate meaning of viral E2-gene for radiosensitivity.
Methods
W12 cells contain episomal HPV 16 genomes, whereas S12 cells, which derive from the W12 line, contain HPV DNA as integrated copies. Clonogenic survival was analyzed using 96-well in vitro test. Using flow cytometry cell cycle analyses were performed. Expression of pRb and p53 were analyzed using intracellular staining.
Results
W12 cells (intact E2 gene) showed a lower survival fraction than S12 cells. W12 cells developed a G2/M block 24 h after irradiation with 2 Gy whereas S12 showed no G2/M bloc. After irradiation S12 cells developed polyploidy and pRb-positive cells decreased. W12 cells showed no change of pRb-positive cells.
Conclusions
Depending on E2 gene status differences in cell cycle regulation might cause radioresistance. The E2/E7/pRb pathway seems to influence HPV-induced radiosensitivity. Our experiments demonstrated an effect of HPV on radiosensitivity of cervical keratinocytes via viral transcription regulator E2 pathway.
doi:10.1186/1748-717X-7-187
PMCID: PMC3542163  PMID: 23134732
Human Papillomavirus; Radiosensitvity; E2-gene; Cervical keratinocytes
8.  Classification of Papillomaviruses (PVs) Based on 189 PV Types and Proposal of Taxonomic Amendments 
Virology  2010;401(1):70-79.
We present an expansion of the classification of the family Papillomaviridae, which now contains 29 genera formed by 189 papillomavirus (PV) types isolated from humans (120 types), non-human mammals, birds and reptiles (64, 3 and 2 types, respectively). To accommodate the number of PV genera exceeding the Greek alphabet, the prefix “dyo” is used, continuing after the Omega-PVs with Dyodelta-PVs. The current set of human PVs are contained within five genera, whereas mammalian, avian and reptile PVs are contained within 20, 3 and 1 genera, respectively. We propose standardizations to the names of a number of animal PVs. As prerequisite for a coherent nomenclature of animal PVs, we propose founding a Reference Center for Animal PVs. We discuss that based on emerging species concepts derived from genome sequences, PV types could be promoted to the taxonomic level of species, but do not recommend implementing this change at the current time.
doi:10.1016/j.virol.2010.02.002
PMCID: PMC3400342  PMID: 20206957
9.  Analysis of Tp53 Codon 72 Polymorphisms, Tp53 Mutations, and HPV Infection in Cutaneous Squamous Cell Carcinomas 
PLoS ONE  2012;7(4):e34422.
Background
Non-melanoma skin cancers are one of the most common human malignancies accounting for 2–3% of tumors in the US and represent a significant health burden. Epidemiology studies have implicated Tp53 mutations triggered by UV exposure, and human papilloma virus (HPV) infection to be significant causes of non-melanoma skin cancer. However, the relationship between Tp53 and cutaneous HPV infection is not well understood in skin cancers. In this study we assessed the association of HPV infection and Tp53 polymorphisms and mutations in lesional specimens with squamous cell carcinomas.
Methods
We studied 55 cases of histologically confirmed cutaneous squamous cell carcinoma and 41 controls for the presence of HPV infection and Tp53 genotype (mutations and polymorphism).
Results
We found an increased number of Tp53 mutations in the squamous cell carcinoma samples compared with perilesional or control samples. There was increased frequency of homozygous Tp53-72R polymorphism in cases with squamous cell carcinomas, while the Tp53-72P allele (Tp53-72R/P and Tp53-72P/P) was more frequent in normal control samples. Carcinoma samples positive for HPV showed a decreased frequency of Tp53 mutations compared to those without HPV infection. In addition, carcinoma samples with a Tp53-72P allele showed an increased incidence of Tp53 mutations in comparison carcinomas samples homozygous for Tp53-72R.
Conclusions
These studies suggest there are two separate pathways (HPV infection and Tp53 mutation) leading to cutaneous squamous cell carcinomas stratified by the Tp53 codon-72 polymorphism. The presence of a Tp53-72P allele is protective against cutaneous squamous cell carcinoma, and carcinoma specimens with Tp53-72P are more likely to have Tp53 mutations. In contrast Tp53-72R is a significant risk factor for cutaneous squamous cell carcinoma and is frequently associated with HPV infection instead of Tp53 mutations. Heterozygosity for Tp53-72R/P is protective against squamous cell carcinomas, possibly reflecting a requirement for both HPV infection and Tp53 mutations.
doi:10.1371/journal.pone.0034422
PMCID: PMC3335843  PMID: 22545084
10.  Differential Regulation of Cutaneous Oncoprotein HPVE6 by wtp53, Mutant p53R248W and ΔNp63α is HPV Type Dependent 
PLoS ONE  2012;7(4):e35540.
UV exposure and p53 mutations are major factors in non-melanoma skin cancer, whereas a role for HPV infections has not been defined. Previous data demonstrated the wtp53-mediated degradation of cutaneous HPV20E6 by caspase-3. ΔNp63α and hot-spot mutant p53R248W conveyed a protective effect on HPV20E6 under these conditions. We demonstrate a differential regulation by wtp53 of the E6 genes of cutaneous types HPV4, HPV5, HPV7, HPV27, HPV38, HPV48, HPV60 and HPV77. Caspase- or proteasome-mediated down-regulation was HPV type dependent. Mutant p53R248W up-regulated expression of all these E6 proteins as did ΔNp63α except for HPV38E6 which was down-regulated by the latter. None of these cellular proteins affected HPV41E6 expression. Ectopic expression of both mutp53R248W and ΔNp63α in the normal NIKS keratinocyte cell line harbouring endogenous p53 and p63however led to a down-regulation of HPV20E6. We demonstrate that HPV20E6 expression in these cells is modulated by additional, yet unidentified, cellular protein(s), which are not necessarily involved in apoptosis or autophagy. We further demonstrate proliferation of HPV20E6-expressing keratinocytes. Levels of proteins involved in cell cycle control, cyclin-D1, cdk6 and p16INK4a, phosphorylated pRB, as well as c-Jun and p-c-Jun, were all increased in these cells. HPV20E6 did not compete for the interaction between p16INK4a with cyclin-D1 or cdk6. Phosphorylation of pRB in the HPV20E6 expressing cells seems to be sufficient to override the cytokenetic block induced by the p16INK4a/pRB pathway. The present study demonstrates the diverse influence of p53 family members on individual cutaneous HPVE6 proteins. HPV20E6 expression also resulted in varying protein levels of factors involved in proliferation and differentiation.
doi:10.1371/journal.pone.0035540
PMCID: PMC3329482  PMID: 22530045
11.  Detection of Human Papillomavirus DNA in Cutaneous Squamous Cell Carcinoma among Immunocompetent Individuals 
The presence of certain types of human papillomavirus (HPV) is a known risk factor for the development of anogenital squamous cell carcinomas (SCCs). A similar association has been hypothesized for cutaneous SCCs, although, to our knowledge, no studies to date have combined sensitive HPV DNA detection techniques with epidemiologic data controlling for known risk factors to explore the association. We designed a case–control study examining HPV prevalence using highly sensitive PCR-detection assays in tissue samples from 85 immunocompetent patients with histologically confirmed SCCs and 95 age-matched individuals without a prior history of skin cancer. A standardized interview was administered to all study subjects to collect information pertaining to potential confounding variables. The overall detection rate of HPV DNA was high in case lesions (54%) and perilesions (50%) and in both sun-exposed normal tissue (59%) and non-sun-exposed normal tissue (49%) from controls. In comparing case tissue to control tissue, there was no differential detection of HPV DNA across various HPV species. However, HPV DNA from β-papillomavirus species 2 was more likely to be identified in tumors than in adjacent healthy tissue among cases (paired analysis, odds ratio = 4.0, confidence interval = 1.3–12.0). The high prevalence of HPV DNA detected among controls suggests that HPV DNA is widely distributed among the general population. However, the differential detection of HPV β-papillomavirus species in tumors among cases suggests that certain HPV types may be involved in the progression of cutaneous SCCs.
doi:10.1038/sj.jid.5701227
PMCID: PMC3268673  PMID: 18185530
12.  The Diversity of Torque Teno Viruses: In Vitro Replication Leads to the Formation of Additional Replication-Competent Subviral Molecules ▿ †  
Journal of Virology  2011;85(14):7284-7295.
The family Anelloviridae comprises torque teno viruses (TTVs) diverse in genome structure and organization. The isolation of a large number of TTV genomes (TTV Heidelberg [TTV-HD]) of 26 TTV types is reported. Several isolates from the same type indicate sequence variation within open reading frame 1 (ORF1), resulting in considerably modified open reading frames. We demonstrate in vitro replication of 12 full-length genomes of TTV-HD in 293TT cells. Propagation of virus was achieved by several rounds of infections using supernatant and frozen whole cells of initially infected cells. Replication of virus was measured by PCR amplification and transcription analyses. Subgenomic molecules (μTTV), arising early during propagation and ranging in size from 401 to 913 bases, were cloned and characterized. Propagation of these μTTV in in vitro cultures was demonstrated in the absence of full-length genomes.
doi:10.1128/JVI.02472-10
PMCID: PMC3126604  PMID: 21593173
13.  E7 Oncoprotein of Novel Human Papillomavirus Type 108 Lacking the E6 Gene Induces Dysplasia in Organotypic Keratinocyte Cultures ▿  
Journal of Virology  2009;83(7):2907-2916.
The genome organization of the novel human papillomavirus type 108 (HPV108), isolated from a low-grade cervical lesion, deviates from those of other HPVs in lacking an E6 gene. The three related HPV types HPV103, HPV108, and HPV101 were isolated from cervicovaginal cells taken from normal genital mucosa (HPV103) and low-grade (HPV108) and high-grade cervical (HPV101) intraepithelial neoplasia (Z. Chen, M. Schiffman, R. Herrero, R. DeSalle, and R. D. Burk, Virology 360:447-453, 2007, and this report). Their unusual genome organization, against the background of considerable phylogenetic distance from the other HPV types usually associated with lesions of the genital tract, prompted us to investigate whether HPV108 E7 per se is sufficient to induce the above-mentioned clinical lesions. Expression of HPV108 E7 in organotypic keratinocyte cultures increases proliferation and apoptosis, focal nuclear polymorphism, and polychromasia. This is associated with irregular intra- and extracellular lipid accumulation and loss of the epithelial barrier. These alterations are linked to HPV108 E7 binding to pRb and inducing its decrease, an increase in PCNA expression, and BrdU incorporation, as well as increased p53 and p21CIP1 protein levels. A delay in keratin K10 expression, increased expression of keratins K14 and K16, and loss of the corneal proteins involucrin and loricrin have also been noted. These modifications are suggestive of infection by a high-risk papillomavirus.
doi:10.1128/JVI.02490-08
PMCID: PMC2655592  PMID: 19153227
14.  Human papillomavirus infection and UV exposure as epidermoid inclusion cyst risk factors in a patient with epidermodysplasia verruciformis? 
Journal of the American Academy of Dermatology  2008;58(5 Suppl 1):S68.e1-S68.e6.
Background
Epidermoid inclusion cysts are common lesions with unclear etiology.
Objective
To examine evidence for human papillomavirus (HPV) infection and UV exposure as risk factors in the formation of epidermoid inclusion cysts.
Methods
Case report with HPV typing of biopsied cysts with polymerase chain reaction.
Results
A patient with darkly-pigmented skin, epidermodysplasia verruciformis (EV) and >250 photodistributed cysts demonstrated HPV 8 and HPV 6 DNA within biopsies of three cysts. One biopsy demonstrated abnormal keratinocytes bridging the follicular infundibulum.
Limitation
This is a case report.
Conclusion
UV exposure and HPV viral infection may be risk factors for epidermoid inclusion cyst formation.
doi:10.1016/j.jaad.2007.01.032
PMCID: PMC2587233  PMID: 18489051
15.  In Vivo and In Vitro Intragenomic Rearrangement of TT Viruses▿  
Journal of Virology  2007;81(17):9346-9356.
The in vitro replication of the Torque teno virus (TT virus) tth8 full-length genome and particle formation in a Hodgkin's lymphoma-derived cell line after transfection with cloned viral DNA were demonstrated. Analyses of the transcription patterns of tth8 and tth7 TT virus isolates in a number of lymphoma and T-cell leukemia cell lines indicated differential additional splicing events and intragenomic rearrangement generating open reading frames which could not be deducted from the genomic sequence. We also demonstrated the presence of rearranged TT virus genomes in vivo in sera taken from pregnant mothers whose children later developed childhood leukemia, as well as sera from control mothers. Control experiments using religated cloned genomic tth8 DNA mixed with cellular DNA did not result in such subviral molecules. These subviral isolates ranged from 172 bp to full-length TT virus genomes. Possible in vivo selection for specific rearranged molecules was indicated by the presence of one isolate (561 bp) in 11 serum samples. It remains to be clarified whether selected rearranged subviral components resulting from specific TT virus types may contribute to the initiation of disease. These data demonstrate new features of TT viruses suggesting possible similarities to plant viruses of the family Geminiviridae, as well as raise questions about the documented plurality and diversity of anelloviruses.
doi:10.1128/JVI.00781-07
PMCID: PMC1951432  PMID: 17596318
16.  E6/E7 Expression of Human Papillomavirus Type 20 (HPV-20) and HPV-27 Influences Proliferation and Differentiation of the Skin in UV-Irradiated SKH-hr1 Transgenic Mice▿  
Journal of Virology  2006;80(22):11153-11164.
The functional role of UV irradiation, in combination with the E6 and E7 proteins of the cutaneous human papillomavirus (HPV) types in the malignant conversion of benign papillomatous lesions, has not been elucidated. Transgenic SKH-hr1 hairless mice expressing HPV-20 and HPV-27 E6 and E7 proteins in the suprabasal compartment were generated and exposed to chronic UV irradiation. Histological and immunohistochemical examination of skin samples revealed enhanced proliferation of the epidermal layers and papilloma formation in both transgenic strains in comparison to what was observed with nontransgenic mice. Squamous cell carcinoma developed in the HPV-20 E6/E7 transgenic line as well as in the HPV-27 E6/E7 transgenic line. Several weeks after cessation of UV-B exposure, enhanced proliferation, as measured by BrdU incorporation, was maintained only in HPV-20 transgenic skin. Keratin 6 expression was increased in the transgenic mice throughout all cell layers. Expression of the differentiation markers involucrin and loricrin was reduced and disturbed. p63α expression was differentially regulated with high levels of cytoplasmic expression in clusters of cells in the granular layer of the skin in the transgenic lines 20 weeks after cessation of UV-B exposure, in contrast to uninterrupted staining in the nontransgenic lines. p53 was expressed in clusters of cells in nontransgenic and HPV-27 transgenic mice, in contrast to an even distribution in a higher number of cells in HPV-20 transgenic animals.
doi:10.1128/JVI.00954-06
PMCID: PMC1642157  PMID: 16971438
17.  Results of the First World Health Organization International Collaborative Study of Detection of Human Papillomavirus DNA†  
Journal of Clinical Microbiology  2006;44(2):571-579.
Twenty-nine laboratories in 12 countries participated in a study to assess the performance of various human papillomavirus (HPV) detection assays through the use of a recombinant HPV DNA standard reagent panel. The panel was designed by a group of HPV experts, and samples were prepared and distributed by the World Health Organization International Laboratory for Standards and Biologicals in The Netherlands. Each panel consisted of 24 coded samples including a dilution series for HPV types 16 and 18, alone or in combination with five other high-risk (HR) HPV types including HPV types 31, 33, 35, 45, and 52, the low-risk HPV type 6, and a negative control. Qualitative assays were generally consistent across laboratories, and most invalid results reflected a lack of HPV test sensitivity. The combined data sets had a proficiency for HPV 16 of 62.5% (15/24) and for HPV 18 of 73.9% (17/23). HPV 31 was the least accurately detected by participating laboratories. Approximately half of participating laboratories failed to detect high concentrations of HPV 31 and, to a lesser extent, to detect HPV types 35, 52, and 6. The panel sample materials offer a source of renewable and reproducible material that could be used in the future development of international standard reagents for calibration of HPV DNA assays and kits.
doi:10.1128/JCM.44.2.571-579.2006
PMCID: PMC1392673  PMID: 16455914
18.  Recognition of Conserved Amino Acid Motifs of Common Viruses and Its Role in Autoimmunity 
PLoS Pathogens  2005;1(4):e41.
The triggers of autoimmune diseases such as multiple sclerosis (MS) remain elusive. Epidemiological studies suggest that common pathogens can exacerbate and also induce MS, but it has been difficult to pinpoint individual organisms. Here we demonstrate that in vivo clonally expanded CD4+ T cells isolated from the cerebrospinal fluid of a MS patient during disease exacerbation respond to a poly-arginine motif of the nonpathogenic and ubiquitous Torque Teno virus. These T cell clones also can be stimulated by arginine-enriched protein domains from other common viruses and recognize multiple autoantigens. Our data suggest that repeated infections with common pathogenic and even nonpathogenic viruses could expand T cells specific for conserved protein domains that are able to cross-react with tissue-derived and ubiquitous autoantigens.
Synopsis
Infectious agents have been discussed as possible triggers for multiple sclerosis (MS). Molecular mimicry, meaning an antigenic similarity between pathogen proteins and self-proteins (also called autoantigens), is one mechanism that can activate autoreactive T cells. To identify potential triggers and autoantigens in MS, the authors of this study determined the specificity of T cell clones (TCCs) from cerebrospinal fluid (CSF) of an MS patient, which were clonally expanded during disease exacerbation. The CSF is in intimate contact with the central nervous system, which is damaged by autoreactive T cells in MS. The authors observed that these TCCs recognize amino acid motifs from functional protein domains that are evolutionarily conserved between viruses, prokaryotes, and eukaryotes. This phenomenon is reminiscent of pattern recognition by the innate immune system via Toll-like receptors, and represents an interesting bridge as to how immune responses against foreign agents may be misdirected against autoantigens. Three TCCs recognize arginine-rich motifs and respond to peptides from the ubiquitous, nonpathogenic Torque Teno virus (TTV), but also from other common viruses and autoantigens. TTV recognition by clonally expanded CSF TCCs, and the demonstration of viral infection in brains of people with MS, suggest that this virus may participate in triggering or sustaining autoimmune diseases such as MS.
doi:10.1371/journal.ppat.0010041
PMCID: PMC1315278  PMID: 16362076
19.  Presence of papillomavirus sequences in condylomatous lesions of the mamillae and in invasive carcinoma of the breast 
Breast Cancer Research  2004;7(1):R1-R11.
Background
Viruses including Epstein–Barr virus (EBV), a human equivalent of murine mammary tumour virus (MMTV) and human papillomavirus (HPV) have been implicated in the aetiology of human breast cancer. We report the presence of HPV DNA sequences in areolar tissue and tumour tissue samples from female patients with breast carcinoma. The presence of virus in the areolar–nipple complex suggests to us a potential pathogenic mechanism.
Methods
Polymerase chain reaction (PCR) was undertaken to amplify HPV types in areolar and tumour tissue from breast cancer cases. In situ hybridisation supported the PCR findings and localised the virus in nipple, areolar and tumour tissue.
Results
Papillomavirus DNA was present in 25 of 29 samples of breast carcinoma and in 20 of 29 samples from the corresponding mamilla. The most prevalent type in both carcinomas and nipples was HPV 11, followed by HPV 6. Other types detected were HPV 16, 23, 27 and 57 (nipples and carcinomas), HPV 20, 21, 32, 37, 38, 66 and GA3-1 (nipples only) and HPV 3, 15, 24, 87 and DL473 (carcinomas only). Multiple types were demonstrated in seven carcinomas and ten nipple samples.
Conclusions
The data demonstrate the occurrence of HPV in nipple and areolar tissues in patients with breast carcinoma. The authors postulate a retrograde ductular pattern of viral spread that may have pathogenic significance.
doi:10.1186/bcr940
PMCID: PMC1064094  PMID: 15642157
areolar tissue; breast carcinoma; papillomavirus
20.  Isolation of Multiple TT Virus Genotypes from Spleen Biopsy Tissue from a Hodgkin's Disease Patient: Genome Reorganization and Diversity in the Hypervariable Region 
Journal of Virology  2004;78(14):7498-7507.
We report the isolation of 24 novel genotypes of TT viruses from a surgically removed spleen of a patient with Hodgkin's disease. The sequence analysis of our 24 isolates revealed the remarkable heterogeneity of TT virus isolates not only from the same patient but also from the same biopsy material. These isolates belong to four phylogenetic groups of TT viruses. Nucleotide sequence analyses revealed five distinct genotypes (tth3, tth4, tth5, tth6, and tth7). The limited variation in sequence identity of the other isolates defines the latter as variants of four of these genotypes. A group of 6 isolates (the tth7 group) revealed a reorganization of open reading frame 1 (ORF1) leading to one larger and a varying number of smaller ORFs. The nucleotide difference of the full-length genomes was less than 1%. A variation of 69 to 97% in amino acids of a second group of 8 isolates (the tth3 group) was restricted to the hypervariable region of ORF1, indicating the existence of a quasi-species. These isolates differed by less than 2% in the remainder of their nucleotide sequences. An alignment of these isolates with 79 previously reported TT virus genotypes permits the proposal of TT virus genera and species within the family Anelloviridae in analogy to a previous proposal for the papillomaviruses (family Papillomaviridae).
doi:10.1128/JVI.78.14.7498-7507.2004
PMCID: PMC434092  PMID: 15220423
21.  The E6 and E7 Proteins of the Cutaneous Human Papillomavirus Type 38 Display Transforming Properties 
Journal of Virology  2003;77(3):2195-2206.
Several studies have suggested the involvement of cutaneous human papillomaviruses (HPVs) in the development of nonmelanoma skin cancers. Here we have characterized the in vitro properties of E7 proteins of three cutaneous HPV types, 10, 20, and 38, which are frequently detected in skin specimens. We show that HPV38 E7 is able to inactivate the tumor suppressor pRb and induces loss of G1/S transition control, a key event in carcinogenesis. In contrast, HPV10 and HPV20 E7 proteins do not display these in vitro transforming activities. We also show that the two early proteins E6 and E7 of HPV38 are sufficient to corrupt the cell cycle and senescence programs in primary cells, inducing active and long-lasting proliferation of primary human keratinocytes, the natural host cells. Our study shows that E6 and E7 of this cutaneous HPV type have transforming activity in primary human cells, suggesting a role for HPV38 infection in skin carcinogenesis. In further support of such a role, we detected HPV38 DNA in approximately 50% of nonmelanoma skin cancers, but only in 10% of healthy skin specimens (P < 0.001).
doi:10.1128/JVI.77.3.2195-2206.2003
PMCID: PMC140944  PMID: 12525654
22.  Degenerate and Nested PCR: a Highly Sensitive and Specific Method for Detection of Human Papillomavirus Infection in Cutaneous Warts 
Journal of Clinical Microbiology  1999;37(11):3545-3555.
The role of human papillomavirus (HPV) in anogenital carcinogenesis is firmly established, but evidence that supports a similar role in skin remains speculative. Immunosuppressed renal transplant recipients have an increased incidence of viral warts and nonmelanoma skin cancer, and the presence of HPV DNA in these lesions, especially types associated with the condition epidermodysplasia verruciformis (EV), has led to suggestions that HPV may play a pathogenic role. However, differences in the specificities and sensitivities of techniques used to detect HPV in skin have led to wide discrepancies in the spectrum of HPV types reported. We describe a degenerate nested PCR technique with the capacity to detect a broad spectrum of cutaneous, mucosal, and EV HPV types. In a series of 51 warts from 23 renal transplant recipients, this method detected HPV DNA in all lesions, representing a significant improvement over many previously published studies. Cutaneous types were found in 84.3% of warts and EV types were found in 80.4% of warts, whereas mucosal types were detected in 27.4% of warts. In addition, the method allowed codetection of two or more distinct HPV types in 94.1% of lesions. In contrast, single HPV types were detected in all but 1 of 20 warts from 15 immunocompetent individuals. In summary, we have established a highly sensitive and comprehensive degenerate PCR methodology for detection and genotyping of HPV from the skin and have demonstrated a diverse spectrum of multiple HPV types in cutaneous warts from transplant recipients. Studies designed to assess the significance of these findings to cutaneous carcinogenesis are under way.
PMCID: PMC85688  PMID: 10523550

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