Human inborn errors of immunity to oncogenic viruses.

Oncoviruses are viruses that can cause tumors. Seven viruses are currently recognized as oncogenic in humans: Epstein Barr virus (EBV), Kaposi sarcoma-associated herpesvirus (KSHV, also known as HHV8), human papillomaviruses (HPVs), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-lymphotropic virus-1 (HTLV-1), and Merkel cell polyomavirus (MCPyV). The clinical phenotypes resulting from infection with these oncoviruses range from asymptomatic infection to invasive cancers. Patients with inborn errors of immunity (IEI) are prone to the development of infectious diseases caused by a narrow or broad spectrum of pathogens, including oncoviruses in some cases. Studies of patients with IEI have deepened our understanding of the non-redundant mechanisms underlying the control of EBV, HHV8 and HPV infections. The human genetic factors conferring predisposition to oncogenic HBV, HCV, HTLV-1 and MCPyV manifestations remain elusive. We briefly review here what is currently known about the IEI conferring predisposition to severe infection with oncoviruses.

Pathogen-associated regulatory non-coding RNAs and oncogenesis.

Among all new cancer cases in 2012, on average, 15.4% were caused by Helicobacter pylori or oncoviruses, including Epstein-Barr virus, human papillomavirus, hepatitis B virus, hepatitis C viruses, Kaposi sarcoma-associated herpesvirus and human T-lymphotropic virus. These pathogens encode a variety of non-coding RNAs, which are important cofactors for oncogenesis. In this review, we focus on recent developments in the study of long and small non-protein-coding RNAs, including microRNAs, of oncogenic pathogens, and discuss their mechanisms of action in the multiple steps of oncogenesis.

Multiplex PCR/mass spectrometry screening of biological carcinogenic agents in human mammary tumors.

BACKGROUND: While many studies have suggested a possible link between breast cancer pathogenesis and infection by viruses, the role of viruses in breast carcinogenesis remains controversial. OBJECTIVES: We analyzed the prevalence of 30 oncogenic human papillomaviruses (HPVs), Epstein-Barr virus (EBV), Kaposi's sarcoma herpes virus (KSHV) and six polyomaviruses in breast tumor specimens. STUDY DESIGN: We analyzed breast specimens from 100 breast cancer patients (group 1) and 50 benign breast disease patients (group 2) from Shaanxi Province in China. We also screened for the viruses in blood samples from the patients and 96 female blood donor volunteers (group 3). RESULTS: EBV, Merkel cell polyomavirus (MCPyV) and HPV-18 were detected in 60, 14 and 2 breast cancer patients, respectively, and EBV and MCPyV were detected in 16 and 1 benign breast disease patients, respectively. EBV and MCPyV were more prevalent in group 1 than in group 2 (EBV: 60.0% vs. 32.0%, p = 0.0012; MCPyV: 14.0% vs. 2.0%; p = 0.02). In contrast, there was no difference in the prevalence of EBV and MCPyV in blood samples between group 1 and group 2, group 1 and group 3. EBV was detected in malignant breast tissue and its presence was confined to the malignant cells using in situ hybridization. CONCLUSIONS: We found that EBV and MCPyV were more prevalent in the tumors of women with breast cancer than in samples from women with benign breast disease. Our results support an etiologic role for EBV in breast cancer pathogenesis in Chinese patients.

Detection of human papillomaviruses of high oncogenic potential in oral squamous cell carcinoma in a Venezuelan population.

OBJECTIVE: The aim of this work was to detect and typify human papillomaviruses (HPV) in oral squamous cell carcinoma (OSCC) in a Venezuelan population. MATERIAL(S) AND METHODS: Eighteen tissue samples were obtained from biopsies, formalin-fixed, and paraffin-embedded; 16 were diagnosed as SCC. We isolated DNA from paraffin-embedded tissue; two to three sections of 5 microm were obtained and resuspended in digestion buffer and proteinase K. Five microliters of the aqueous phase was used for polymerase chain reaction (PCR). The PCR for HPV amplification was carried out with consensus primers for L1 region (MY09 and MY11) and beta-globin gene was used as internal control. The viral types were determined by molecular hybridization with a mix of probes for high/intermediate and low HPV oncogenic risk types. RESULTS: The HPV-DNA was detected in 50% (eight of 16) of the SCC cases. Of these HPV-DNA-positive samples, 68% were histopathologically diagnosed as moderately differentiated SCC. The most common anatomical location was the alveolar ridge mucosa. All positive biopsies contained high oncogenic HPV types. CONCLUSIONS: We observed a high prevalence of HPV infection of high oncogenic potential types in patients with SCC in our studied group. The moderately differentiated SCCs were more associated to HPV infection. These differences could be influenced by nutritional, environmental and genetical factors in our population but further studies should be carried out to determine these aspects.

The E1A N terminus (aa 1-29) of the highly oncogenic adenovirus type 12 harbours a trans-activation function not detectable in the non-oncogenic serotype 2.

Early region 1A (E1A) of adenoviruses (Ad) codes for potent activator and repressor molecules which are involved in the regulation of viral and cellular gene expression. Gene regulatory functions of E1A proteins are mainly located in their conserved regions (CR) 1 to 3. In addition to the CRs, specific amino acids (aa) of the N-terminal end play an important role in some gene regulatory functions. We describe here the identification and characterization of a novel trans-activation domain which is located in the non-conserved N-terminal end of Ad12 E1A, namely aa 1-29. Fusion of this region to the DNA-binding domain of the yeast transcription factor Gal4 generates a strong trans-activator which induces gene expression of reporter constructs in dependence on Gal4 DNA-binding sites. Furthermore, transient expression assays using the physiological E1A-responsive adenoviral E2 early promoter revealed that the N terminus is involved in its activation. The gene regulatory function of the N terminus is specific for E1A proteins of the highly oncogenic serotype Ad12, as the respective E1A N terminus of the non-oncogenic serotype Ad2 is unable to activate the expression of the reporter gene as Gal4 fusion protein. Moreover, deletion mutant analyses demonstrate that Ad12 E1A proteins carry three independently acting activation domains: (1) aa 1-29, (2) CR1 and (3) CR3.

[Virus and human oncogenesis]. / Virus et cancérogenèse humaine.

Only a limited number of human viruses have been shown to have oncogenic properties, including the retrovirus HTLV1 and 2, the hepatitis B virus (HBV), the Epstein-Barr virus (EBV), and some human papillomas virus (HPV). Epidemiologic and molecular biological studies have shown that these viruses were involved as cofactors in the multistep process of carcinogenesis. Viral DNA probes or antibodies against viral proteins can prove to be useful tools for diagnostic (HTLV1, EBV, HBV) or prognosis (HPV) of some cancers. A better knowledge of these viruses may also have therapeutic implications in a not too distant future such as the vaccination against HBV in order minimize the incidence of hepatocellular carcinoma in endemic countries.

Viruses in the aetiology of oral carcinoma? Examination of the evidence.

This paper examines the evidence for an aetiological role for viruses in the development of oral carcinoma. Several viruses have been sought in oral cancer and evidence found for some, particularly herpes simplex and human papillomavirus. However, the evidence also suggests that these viruses are ubiquitous agents and a number of criteria must be met before these potentially oncogenic agents can reliably be implicated in human carcinogenesis. In contrast, there is no evidence that viruses such as adenovirus, Epstein-Barr virus, and retroviruses play any role in oral carcinogenesis.

The multifaceted retrovirus.

I have attempted to illustrate the many different properties of retroviruses and their presence in a wide variety of animal species including humans. Since the turn of this century, progress in the field of retrovirology has been noteworthy and many new and important scientific observations have been made (Table 7). Along the way, certain dogmas were replaced with new tenets. The recent recognition of retroviruses associated with human cancer and immunodeficiency places them into consideration as potential agents responsible for other human diseases such as autoimmunity and multiple sclerosis. Not only can retroviruses be oncogenic or cytopathic agents but they can also exist highly conserved as endogenous genes in the chromosomal DNA of many different species and not cause disease. In fact, this latter group appears to be predominant, suggesting their role in normal developmental processes and as progenitors of the pathogenic types. The virus-like genomes recognized in Drosophila and other lower animal species could be examples of this fact and may represent important biological entities throughout nature. The genetic material of retroviruses resembles transposons and may reflect the ability of these viruses to be passed within the host and to affect the evolutionary pathway. They could, as transposable elements, be transmitted as well to many different animal species. By their ability to move within the genetic machinery of the cell, these viruses could influence development in animals through promotion, enhancement, or suppression of specific cellular genes. This idea has been proposed for the noninfectious type A particles that have been observed to show these effects in cultured cells. One important observation is that the effect of retroviruses on cells has a varied pattern which may be emphasized by one group (e.g., vacuolization by foamy virus) or shared by other groups (e.g.., syncytial cell formation by type C and type D oncovirinae, spumavirinae, and lentivirinae) (Table 6). Moreover, the heterogeneity of the lentiviruses and the transduction of normal cellular genes by many of the oncogenic viruses indicate the changes that can occur as retroviruses infect and replicate within the cell. The overview is very informative. Virus-cell interaction can lead to biological expressions that depend on the phenotype of the cell and the viral genetic structure. Throughout its existence in nature the retrovirus has been evolving, conserving certain features while developing new ones with different properties; it clearly emerges as a multifaceted agent.

Genetic relatedness between intracisternal A particles and other major oncovirus genera.

Intracisternal A particles represent a major oncovirus genus. By reciprocal hybridization between molecularly cloned A particles and representatives of other oncovirus genera, we established pol gene homology with type B, type D and avian type C viruses. The most extensive homology was with mammalian type D viruses. The transcriptional orientation of the IAP genome was determined, as well as evidence indicating that its pol gene, which is apparently defective, contains coding regions for both reverse transcriptase and endonuclease proteins.

[Human oncogenic viruses]. / Les virus oncogènes humains.

Human oncogenic viruses are ubiquitous pathogens which only in frequently exhibit their malignant potential under natural conditions. They are either ARN viruses, also called retroviruses, of which little is known in man, or DNA viruses belonging to various families (papovavirus, adenovirus, herpes virus, hepatitis B virus), some of which are very specifically associated with certain human carcinomas. In vitro, these viruses induce "cell transformation" producing malignant cells with unregulated growth. In vivo, in man as well as in animals, viral oncogenesis requires multiple cofactors so that the transformed cell can escape control mechanisms.

Viruses and cancer risk in man.

The present state of tumor virus research in man is analysed in order to evaluate the cancer risk by viruses in man. For most of the viruses isolated from human tumorous or normal tissues and similar to oncogenic viruses of animals the participation as causative agent in the multifactorial process of cancer induction, promotion and realization in man is not yet established. This holds true for DNA viruses (paillomaviruses, SV 40-related viruses, Herpesvirus 2, hepatitis B virus) as well as for the retroviruses. There are, however, data which give circumstantial evidence for the association of members of these groups of viruses with certain types of human tumors. The foremost candidate as human tumor virus is the Epstein-Barr virus--an essential causative factor for Burkitt's lymphoma and nasopharyngeal carcinomas.

A marsupial oncovirus?

A virus-like particle was observed in two continuous cell lines derived from the marsupial Sminthopsis crassicaudata (Fat-tailed Dunnart). The development of the particle was similar to the development of D-type oncoviruses. Initially, a crescentof nucleoid material was observed near the nucleus in the region of the Golgi apparatus. This crescent developed into a doughnut-shaped-A-type particle which migrated through the cytoplasm towards the cell membrane where it budded either into a smooth membrane cytoplasmic vacuole or from the cell membrane. Only enveloped A-type particles were observed; no mature B-type, C-type or D-type particles were detected.

Comparative pathogenesis studies with oncogenic and nononcogenic Marek's disease viruses and turkey herpesvirus.

An apparently nononcogenic Marek's disease virus (SB-1) and turkey herpesvirus could be readily isolated from spleen, bursa of Fabricius, thymus, and peripheral blood lymphocytes of chickens beginning 4 to 6 days after inoculation, but unlike infections with two isolates of oncogenic Marek's disease virus (JM-10 and CU-2), virus replication in these cells was rare, and necrosis in the organs was essentially absent. Splenic enlargement was observed regularly during the first 4 to 11 days after inoculation, and Marek's disease tumor-associated surface antigen was observed on splenic and other lymphocytes in the four viral inoculation groups. Cellular cytotoxicity of splenic lymphocytes was demonstrated in vitro with cultured Marek's disease tumor cells (MSB-1 lymphoblastoid cell line) as the target in a chromium-release assay. The four viral infections induced sensitized lymphocytes.