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.

Oncornavirus: isolation from a squirrel monkey (Saimiri sciureus) lung culture.

An oncornavirus isolated from a squirrel monkey (Saimiri sciureus) lung culture has a density of 1.16 to 1.17 grams per milliliter, contains 70S RNA, and has an RNA-directed DNA polymerase that prefers Mg2+ over Mn2+ in an assay in which polyribocytidylate - oligodeoxyguanylate (12-18) is used as a synthetic template. Morphologically, the virus resembles Mason-Pfizer monkey virus but is antigenically distinct from this virus. The virus grows in cells of human, chimpanzee, rhesus monkey, canine, and mink origin, but not cells of squirrel monkey origin. On the basis of its properties, the newly isolated virus can be classified as a retravirus.

Molecular relatedness of mammalian RNA tumor viruses as determined by DNA hybridization.

Each of six mammalian C-type viruses-including two feline leukemia viruses, three murine leukemia viruses, and the human "candidate" virus RD-114-can be distinguished from each other by hybridizing DNA synthesized by viral reverse transcriptase with viral RNA. Characterization of the DNA . RNA hybrids by hydroxylapatite chromatography revealed nucleotide sequence diversity among the viruses, detectable both by the amount of cross-hybridization and by the decreased thermal stability of heterologous hybrids.

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.

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.

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: IV. The viruses.

Speculations are developed for a mechanism by which oncogenic viruses can induce alterations in cells allowing them to express embryonic genes. It is suggested that if viral deoxyribonucleic acid, directly or via ribonucleic acid directed deoxyribonucleic acid polymerase activity becomes inserted at particular euchromatin - heterochromatin junctions of quasidifferentiated stem-like cells, then deheterochromatization may result, causing in turn derepression of genes for acidic protein phosphokinases. This sets into motion a series of events including altered acid protein repressors of embryonic genes which are repressed by uniquely weak type repressors. This explains how viruses can act as specific embryonic gene-inducing agents similar to chemical inducing agents such as the hepatocarcinogen ethinine.

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.

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.

[Viruses and brain tumors (author's transl)].

This brief review paper deals mainly with oncogenic DNA viruses originally isolated from human patients, i.e., human adenoviruses and human papova JC viruses. Human adenovirus type 12 was first isolated in 1953 in cell cultures derived from the adenoids of infected children. Since then, 32 antigenic types of human adenovirus have been identified. At least eight serotypes (12, 18, 31, 3, 7, 14, 16, and 21) are now known to be capable of producing tumors in newborn rodents. A direct causal relationship between a human adenovirus and malignant transformations in target cells (sensory neuronal precursors) has been definitely established by the development of a medullo-epitheliomatous neoplasm in the brain and spinal cord of an outbred strain of CD rats at as high an incidence as 90%. Intraocular inoculation of adenovirus in newborn rats within one week also has produced typical retinoblastomatous neoplasms. The remarkably uniform histopathologic appearance of all these malignancies in nervous tissue can be attributed to a primitive neuro-epitheliomatous neoplasm derived from sensory microneuron precursors that densely populate both the ventricular zone and the premature sensory retina at the point of virus inoculation. All of these brain and retinal tumors appear to share a common tumor phenotype, as all tumor cells contain cilia with the same morphology (a 9+0 pattern of doublets associated with a pair of centrioles). The production of adenovirus tumor-specific neoantigen (T), an earmark of the viral genome, can be regularly demonstrated by the immunofluorescein microscopic procedure. All transformed cells within both the ventricular zone and the retinal ganglion cell anlage thus appear to continue the production of (T) antigens. These findings lead us to assume that the target cell determinants in adenovirus tumorigenesis may reside in differentiating microneuron precursors ordained for the sensory neuronal complex.

[Comparative antigenic analysis of J-96 cell oncornavirus and Mason-Pfizer virus from a spontaneous monkey mammary tumor]. / Sravnitel'nyi antigennyi analiz onkornavirusov kletok J-96 i virusa Mézon-Pfaizera iz spontannoi opukholi molochnoi zhelezy obez'ian

A comparative study of the antigenic structure of oncornavirus of J-96 cells and Mason-Pfizer virus (M-PVM) isolated from cells of M. rhesus spontaneous mammary tumour was carried out using immunodiffusion in agar, immune autoradiography and indirect immunofluorescence procedures. Immune rabbit serum to disrupted J-96 virus detected by agar immunodiffusion in preparations or purified virus three soluble antigens one of which was identical to group-specific M-PVM antigen.

[Human D(B) type virus: comparison of D(B) type virus antigens with antigens of oncornaviruses of different origins]. / Virus tipa D(B) cheloveka: sravnenie antigenov étogo virusa s antigenami onkornavirusov razlichnogo proiskhozhdeniia

It was found by the immunodiffusion test that the D(B) type virus isolated from human cell lines and Mason-Pfizer monkey virus (M--PMV) contained common group-specific antigen(s). No cross-reaction was demonstrated between this D(B) type virus and C type oncornaviruses of various origins.

[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.

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.