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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. [ABSTRACT FROM AUTHOR]

Focuses on human pathogenic papillomaviruses (HPV). Distribution of HPV infections; Development of proliferative lesions; Viral types; Genome structure; Methods of HPV detection; Genetic predisposition for warts; Immortalization and transformation by HPV; Malignant progression of HPV-immortalized cells; Role of HPV in human cancers; Immune response; HPV infections and longevity.

Consumption of Eurasian bovine meat and milk has been associated with cancer development, in particular with colorectal cancer (CRC). In addition, zoonotic infectious agents from bovine products were proposed to cause colon cancer (zur Hausen et al., 2009). Bovine meat and milk factors (BMMF) are small episomal DNA molecules frequently isolated from bovine sera and milk products, and recently, also from colon cancer (de Villiers et al., 2019). BMMF are bioactive in human cells and were proposed to induce chronic inflammation in precancerous tissue leading to increased radical formation: for example, reactive oxygen and reactive nitrogen species and elevated levels of DNA mutations in replicating cells, such as cancer progenitor cells (zur Hausen et al., 2018). Mouse monoclonal antibodies against the replication (Rep) protein of H1MSB.1 (BMMF1) were used to analyze BMMF presence in different cohorts of CRC peritumor and tumor tissues and cancer-free individuals by immunohistochemistry and Western blot. BMMF DNA was isolated by laser microdissection from immunohistochemistry-positive tissue regions. We found BMMF Rep protein present specifically in close vicinity of CD68+ macrophages in the interstitial lamina propria adjacent to CRC tissues, suggesting the presence of local chronic inflammation. BMMF1 (modified H1MSB.1) DNA was isolated from the same tissue regions. Rep and CD68+ detection increased significantly in peritumor cancer tissues when compared to tissues of cancer-free individuals. This strengthens previous postulations that BMMF function as indirect carcinogens by inducing chronic inflammation and DNA damage in replicating cells, which represent progress to progenitor cells for adenoma (polyps) formation and cancer. [ABSTRACT FROM AUTHOR]

Abstract: Infections during pregnancy have been suggested to be involved in childhood leukemias. We used high-throughput sequencing to describe the viruses most readily detectable in serum samples of pregnant women. Serum DNA of 112 mothers to leukemic children was amplified using whole genome amplification. Sequencing identified one TT virus (TTV) isolate belonging to a known type and two putatively new TTVs. For 22 mothers, we also performed TTV amplification by general primer PCR before sequencing. This detected 39 TTVs, two of which were identical to the TTVs found after whole genome amplification. Altogether, we found 40 TTV isolates, 29 of which were putatively new types (similarities ranging from 89% to 69%). In conclusion, high throughput sequencing is useful to describe the known or unknown viruses that are present in serum samples of pregnant women. [Copyright &y& Elsevier]

Abstract: 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 is 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 we do not recommend implementing this change at the current time. [Copyright &y& Elsevier]

Abstract: Infection of a human T-cell leukaemia cell line (HSB-2) with HHV-6 led to the induction of exosome-like-particles attached to newly formed HHV-6 enveloped particles and to amplification of a 1642 bp molecule consisting of a partial human endogenous retrovirus (HERV)-E polymerase gene and repetitive sequences. We initiated an analysis of transcriptional patterns of predicted genes from HERV-E sequences in normal and malignant haematopoietic cells. Transcription patterns of regions corresponding to gag, pol and env genes at different chromosomal loci varied among cell types tested. Several specific transcripts were only observed in malignant haematopoietic cells and transcriptional activity varied among different malignant cell types. A transcript of 7.1 kb spanning the complete gag, pol and env gene region, originating from chromosome 8p23, was identified in normal peripheral blood cells and cells of the chronic myeloid leukaemia cell line K562. Our study describes new active HERV-E sequences and new loci throughout the human genome. [Copyright &y& Elsevier]

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.Journal of Investigative Dermatology (2008) 128, 1409–1417; doi:10.1038/sj.jid.5701227; published online 10 January 2008 [ABSTRACT FROM AUTHOR]

Chronic inflammation, linked to the presence of bovine milk and meat factors (BMMFs) and specific subsets of macrophages, results in oxygen radical synthesis and induction of mutations in DNA of actively replicating cells and replicating single stranded DNA. Cancers arising from this process have been characterized as indirect carcinogenesis by infectious agents (without persistence of genes of the agent in premalignant or cancers cells). Here, we investigate structural properties of pleomorphic vesicles, regularly identified by staining peritumor tissues of colorectal, lung and pancreatic cancer for expression of BMMF Rep. The latter represents a subgroup of BMMF1 proteins involved in replication of small single-stranded circular plasmids of BMMF, but most likely also contributing to pleomorphic vesicular structures found in the periphery of colorectal, lung and pancreatic cancers. Structurally dense regions are demonstrated in preselected areas of colorectal cancer, after staining with monoclonal antibodies against BMMF1 Rep. Similar structures were observed in human embryonic cells (HEK293TT) overexpressing Rep. These data suggest that Rep or Rep isoforms contribute to the structural formation of vesicles., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Exemplified by infections with bovine meat and milk factors (BMMFs), this manuscript emphasizes the different mechanistic aspects of infectious agents contributing to human cancers by "direct" or "indirect" interactions. The epidemiology of cancers linked to direct carcinogens (e.g., response to immunosuppression) differs from those cancers linked with indirect infectious interactions. Cancers induced by direct infectious carcinogens commonly increase under immunosuppression, whereas the cancer risk by indirect carcinogens is reduced. This influences their responses to preventive and therapeutic interferences. In addition, we discuss their role in colon, breast and prostate cancers and type II diabetes mellitus. A brief discussion covers the potential role of BMMF infections in acute myeloid leukemia.

Red meat and dairy products have frequently been suggested to represent risk factors for certain cancers, chronic neurodegenerative diseases, and autoimmune and cardiovascular disorders. This review summarizes the evidence and investigates the possible involvement of infectious factors in these diseases. The isolation of small circular single-stranded DNA molecules from serum and dairy products of Eurasian Aurochs (Bos taurus)-derived cattle, obviously persisting as episomes in infected cells, provides the basis for further investigations. Gene expression of these agents in human cells has been demonstrated, and frequent infection of humans is implicated by the detection of antibodies in a high percentage of healthy individuals. Epidemiological observations suggest their relationship to the development multiple sclerosis, to heterophile antibodies, and to N-glycolylneuraminic acid (Neu5Gc) containing cell surface receptors.

A possible role for infections of the pregnant mother in the development of childhood acute leukemias and lymphomas has been suggested. However, no specific infectious agent has been identified. Offspring of 74,000 mothers who had serum samples taken during pregnancy and stored in a large-scale biobank were followed up to the age of 15 years (750,000 person years) through over-generation linkages between the biobank files, the Swedish national population and cancer registers to identify incident leukemia/lymphoma cases in the offspring. First-trimester sera from mothers of 47 cases and 47 matched controls were retrieved and analyzed using next generation sequencing. Anelloviruses were the most common viruses detected, found in 37/47 cases and in 40/47 controls, respectively (OR: 0.6, 95% CI: 0.2-1.9). None of the detected viruses was associated with leukemia/lymphoma in the offspring. Viremia during pregnancy was common, but no association with leukemia/lymphoma risk in the offspring was found., (© 2015 UICC.)

The analysis of published epidemiological data on colon and breast cancer reveals a remarkable concordance for most regions of the world. A low incidence for both cancers has been recorded in Mongolia and Bolivia. Discrepant data, however, have been reported for India, Japan and Korea. In India, the incidence of breast cancer is significantly higher than for colon cancer, in Japan and Korea colon cancer exceeds by far the rate of breast cancer. Here, studies are summarized pointing to a species-specific risk for colon cancer after consumption of beef originating from dairy cattle. Uptake of dairy products of Bos taurus-derived milk cattle, particularly consumed at early age, is suggested to represent one of the main risk factors for the development of breast cancer. A recent demonstration of reduced breast cancer rates in individuals with lactose intolerance (Ji et al., Br J Cancer 2014; 112:149-52) seems to be in line with this interpretation. Species-specific risk factors for these cancers are compatible with the transmission of different infectious factors transferred via meat or dairy products. Countries with discordant rates of colon and breast cancer reveal a similar discordance between meat and milk product consumption of dairy cattle. The recent isolation of a larger number of novel presumably viral DNAs from serum, meat and dairy products of healthy dairy cows, at least part of them infectious for human cells, deserves further investigation. Systemic infections early in life, resulting in latency and prevention of subsequent infections with the same agent by neutralizing antibodies, would require reconsideration of ongoing prospective studies conducted in the adult population., (© 2015 UICC.)

The search for infectious agents playing a role in human carcinogenesis and their identification remain important issues. This could provide clues for a broader spectrum of cancers preventable by vaccination and accessible to specific therapeutic regimens. Yet, the various ways of interacting among different factors functioning synergistically and their different modes of affecting individual cells should bring to question the validity of the term "causation". It also should put a word of caution into all attempts to summarize criteria for "causality" of infectious agents in cancer development. At least in the opinion of these authors, we would be much better off avoiding these terms, replacing "causal factor" by "risk factor" and grading them according to their contribution to an individual's cancer risk., (Copyright © 2015. Published by Elsevier Inc.)

The search for infectious agents playing a role in human carcinogenesis and their identification remain important issues. This could provide clues for a broader spectrum of cancers preventable by vaccination and accessible to specific therapeutic regimens. Yet, the various ways of interacting among different factors functioning synergistically and their different modes of affecting individual cells should bring to question the validity of the term "causation". It also should put a word of caution into all attempts to summarize criteria for "causality" of infectious agents in cancer development. At least in the opinion of these authors, we would be much better off avoiding these terms, replacing "causal factor" by "risk factor" and grading them according to their contribution to an individual's cancer risk., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Acceptance of an official classification for the family Papillomaviridae based purely on DNA sequence relatedness, was achieved as late as 2003. The rate of isolation and characterization of new papillomavirus types has greatly depended on and subjected to the development of new laboratory techniques. Introduction of every new technique led to a temporarily burst in the number of new isolates. In the following, the bumpy road towards achieving a classification system combined with the controversies of implementing and accepting new techniques will be summarized. An update of the classification of the 170 human papillomavirus (HPV) types presently known is presented. Arguments towards the implementation of metagenomic sequencing for this rapidly growing family will be presented., (© 2013 Elsevier Inc. All rights reserved.)

The E6 and E7 proteins of human papillomaviruses (HPV) play a crucial role in the pathogenesis of malignant tumors. E6 protein of high-risk mucosal papillomaviruses targets a number of proteins for proteosomal degradation through complex formation with ubiquitin ligase E6AP. These proteins include, amongst others, p53, paxillin and PDZ-domain proteins e.g. Dlg and MAGUK. The mechanism by which the E6 protein of cutaneous HPV types interacts with cellular proteins to induce either benign or malignant cutaneous lesions, has not been elucidated, although extensive ultraviolet exposure and mutated p53 (hot-spot mutations) are known to be associated with non-melanoma skin cancer. We demonstrate two mechanisms in which HPV20E6 may be involved in the infected cell. One pathway is the wtp53 mediated degradation of HPV20E6 through caspase-3. Mutated p53R248W and Delta Np63 alpha, as well as other unknown proteins involved in proteosome-dependent degradation, convey a protective effect on HPV20E6 under these conditions. This unveils a remarkable opposite regulation to the well-known mechanism of E6-E6AP mediated degradation of p53 for mucosal HPV types. In a second interaction, ectopically expressed HPV20E6 induces cleavage of procaspase-3 to active caspase-3. We demonstrate, in addition, in vivo binding of HPV20E6 to the intermediate filament vimentin., ((c) 2008 Wiley-Liss, Inc.)

Epidermoid inclusion cysts are common lesions with unclear etiology. We sought to examine evidence for human papillomavirus (HPV) infection and ultraviolet light (UV) exposure as risk factors in the formation of epidermoid inclusion cysts. We performed HPV typing of biopsied cysts with polymerase chain reaction for a patient with darkly-pigmented skin, epidermodysplasia verruciformis (EV) and more than 250 photodistributed cysts. HPV types 8 and 6 DNA was demonstrated within biopsy specimens of 3 cysts. In one biopsy specimen, abnormal keratinocytes bridging the follicular infundibulum were seen. We concluded that UV exposure and HPV viral infection may be risk factors for the formation of epidermoid inclusion cysts.

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.