Rabbit Papilloma Research Articles

Interaction of a simian papovavirus and adenoviruses. I. Induction of adenovirus tumor antigen during abortive infection of simian cells.

Feldman, Lawrence A. (Baylor University College of Medicine, Houston, Tex.), Janet S. Butel, and Fred Rapp. Interaction of a simian papovavirus and adenoviruses. I. Induction of adenovirus tumor antigen during abortive infection of simian cells. J. Bacteriol. 91:813-818. 1966.-Adenovirus types 2, 7, and 12 undergo an abortive growth cycle in green monkey kidney cells; they induce the formation of adenovirus tumor antigen, but synthesis of adeno capsid antigen and infectious adenovirus was observed only when cultures were concomitantly infected with a simian papovavirus (SV40). Several other viruses, including herpes simplex and measles which replicate in monkey cells, and rabbit papilloma and human wart papovaviruses which do not, failed to stimulate adenovirus replication in the monkey cells. Adenovirus tumor antigen was detected 8 to 10 hr postinfection by immunofluorescent techniques. The antigen induced by adenovirus types 2 and 7 appeared as intranuclear masses; adenovirus type 12 tumor antigen also appeared as cytoplasmic and nuclear flecks. Sera from hamsters bearing tumors induced by adenovirus type 12 cross-reacted with tumor antigens induced by types 2 and 7 but not with antigens induced by SV40.

A study of human papilloma virus DNA

The DNA of human papilloma virus has been examined by a variety of physical techniques. The action of pancreatic deoxyribonuclease on the DNA gives rise to three discrete components, and then to a heterogeneous distribution of fragments. It is suggested that the three components are the supercoiled circular form, simple circular form and linear form of the same molecule. If this is accepted, then the molecular weight of the DNA, calculated from sedimentation coefficient, would be 5·3×106, rather than 7·1×106 as previously estimated. Hybridization studies with human papilloma virus DNA and Shope rabbit papilloma virus DNA using synthetic RNA did not reveal any similarity of base sequence between the two DNA's.

The structure of viruses of the papilloma-polyoma type: III. Structure of rabbit papilloma virus with an appendix on the topography of contrast in negative-staining for electron-microscopy

Unfractionated preparations of rabbit papilloma virus have been examined in the electron-microscope by the method of negative-staining. As in our previous study on human wart virus ( Klug & Finch, 1965 ), we find that the majority of particle images arise by contrast by the negative stain of surface detail from both sides of the virus particles, but a proportion of predominantly “one-side” images occurs. An analysis of the latter proves that the outer shell of the particle has the symmetry of the T = 7 (laevo) icosahedral surface lattice ( Caspar & Klug, 1962 ) and is composed of 72 morphological units. The lattice type is therefore the same as that of human wart virus but of different hand. The structure is further confirmed by the fact that several distinctive types of images can be analysed as “two-side” images which are explicable only on the basis of the same model. These images are identical in type to the “two-side” images we reported in the case of human wart virus, as is to be expected, since the sense of hand makes no difference to a “two-side” image. In addition to the normal full virus particles, empty shells and abnormal particles previously reported by other workers, we have observed a class of empty spherical particles which are distinctly smaller (apparent diameter 380 A) than the normal empty particles (∼ 500 A), and which have fewer morphological units. We have also drawn up a tentative scheme of classification of the abnormal or variant types of particle: (i) apparently elongated versions of the normal virus particle; (ii) tubular particles of diameter similar to the virus particle; (iii) tubular particles of about 350 A diameter; and (iv) the small particles referred to above. In the Appendix we describe an objective method of determining from which side of the virus particle the prevailing contrast of the negative stain originates in those cases where a dominantly “one-side” image is produced. The results show that in the case of both human and rabbit papilloma virus particles, it is the side nearer the carbon substrate which is dominantly contrasted. This fact has enabled us to determine the absolute sense of the hand which is present in the T = 7 lattice of these viruses. The results also indicate that the virus particles are flattened to a varying extent on the electron-microscope grid, and enable semiquantitative estimates to be made of the degree of flattening.

Use of the shope papilloma virus-induced arginase as a biochemical marker in vitro

Data are presented which support the view that infection of cell cultures of cotton-tail rabbit skin by rabbit papilloma virus (Shope) results in an enhanced arginase activity while only slight arginase activity could be found in control cell cultures. This confirms the original observations of Rogers, who isolated an arginase from virus-induced domestic and wild rabbit papilloma tissue obtained from the intact host while little or no arginase activity could be found in control skin. The ability of the Shope papilloma virus to induce an arginase in cell culture has an additional important impact. Thus far, infectious virus cannot be recovered from cell culture systems and the identification of this arginase provides an index of infection of cells in culture that was previously not available.

A study of Shope papilloma virus DNA

The DNA of Shope rabbit papilloma virus has been shown to exist in two forms with the same molecular weight but different sedimentation coefficients, 21 s and 28 s. It is suggested that the 28 s component has the form of a double-stranded ring and that the 21 s component is a linear molecule formed by opening the ring at some specific point.

Chromosome Studies of Virus-Induced Rabbit Papillomas and Derived Primary Carcinomas

Chromosome Studies of Virus-Induced Rabbit Papillomas and Derived Primary Carcinomas

A comparative study of polyoma and papilloma viruses

Polyoma, Shope rabbit papilloma, bovine papilloma, canine papilloma, and human papilloma viruses and their nucleic acids were studied by electron microscopy and analytical centrifugation. Polyoma virus was found to be different, both in size and nucleic acid properties, from the papilloma viruses. The four papilloma viruses were similar to each other in most respects but differed significantly in the base composition of their nucleic acids.

DIRECT COUNTING OF THE CAPSOMERES IN POLYOMA AND PAPILLOMA VIRUSES.

Abstract A method is described for the determination of the number of capsomeres per particle in polyoma, rabbit papilloma, and human papilloma viruses by direct counting of capsomeres in groups derived from disintegrated capsids. For all three viruses the peak of the distribution of the capsomere numbers was in the region of 40. The distributions are consistent with a capsomere number of 42 for these viruses.

TRANSFORMATION OF BOVINE TISSUE CULTURE CELLS BY BOVINE PAPILLOMA VIRUS.

SEVERAL viruses of the papovavirus group, namely, polyoma, SV–40, and rabbit papilloma viruses, produce hereditable morphological alterations—‘transformation’ —of appropriate tissue culture cells1. We have found that another member of this group, the bovine papilloma virus, produces cellular alterations and proliferation in certain bovine tissue culture cells after a very short latent period.

Infectivity Experiments with Nucleic Acids of the Shope Rabbit Papilloma and Derived Carcinomas

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Studies of the mechanism of action of the Shope rabbit papilloma virus. I. Concerning the nature of the induction of arginase in the infected cells.

These studies make plain that the Shope papilloma virus induces the production of an arginase in rabbit squamous epithelium, and provide evidence that the information for the synthesis of the enzyme is derived from the virus rather than the rabbit. This form of induction is therefore different from that brought about by chemicals such as galactosides (36). Striking differences were shown between the physiochemical properties of Shope virus-induced arginase and other arginases of domestic and Kansas cottontail rabbits. The absence of a requirement for manganese suggests the mechanism of splitting off urea from arginine by papilloma arginase probably differs from that of previously described arginases. These findings (particularly the experiments in which it was demonstrated that papilloma growth could be greatly reduced by giving animals supplemental arginine in the presence of small amounts of the arginase inhibitor, canavanine) provide evidence that suggests the following mechanism of action for the virus: viral DNA introduces into rabbit epithelium the information for the synthesis of an arginase for which the cells have no control mechanism. The arginase depletes cellular arginine and, in turn, the synthesis of arginine-rich nuclear histones (2), thereby freeing the nucleus for greater synthetic activity (4, 35), which results in more rapid growth of the papilloma cells. Domestic rabbit papillomas induced with purified virus derived from wild rabbit papillomas were shown to contain an antigen which reacts immunologically like a wild rabbit antigen. It was distinct from the arginase, the protein coat of the virus, and the Vx-2 antigen. The presence of the wild rabbit antigen seems indicative of integration of the virus DNA in the host genome of the wild rabbit. Other incidental findings include the description of a simple method, accurate to within 1 per cent, for determining the partial specific volume of a protein, and the description of a modification of the Richards and Schachman method (9) enabling the determination of the molecular weight and homogeneity of a protein with as little as 0.25 mg and with an accuracy of 2 per cent.

Studies on the virus of rabbit papilloma. 1. Methods of assay.

SUMMARYMethods for the accurate assay of rabbit papilloma virus and its antibody are described. Viral infectivity is titrated by a technique in which up to fifty discrete tumours may be counted on a single inoculation site. Neutralizing antibody is measured with considerable accuracy by determining the dilution of serum producing a 50 p.c. reduction in tumour count. A complement fixation test designed to economize on reagents permits the quick and accurate titration of RPV antigen and antibody.Some of the relationships between tumours, infectious virus, antigen and antibody in naturally and experimentally infected rabbits are examined.

Infectivity Experiments With Nucleic Acids of the Shope Rabbit Papilloma and Derived Carcinomas2

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Organ cultures of newborn rabbit skin affected by rabbit papilloma virus.

Small fragments of newborn rabbit skin were exposed to papilloma virus and transferred to tissue culture. Control cultures were treated the same way, but without addition of the virus. These cultures were then followed for 4 weeks. During the first ten days, the number of epidermal elements declined gradually in both test and control cultures. From the 10th day on, however, a marked proliferation of the remaining epidermal cells was observed in cultures exposed to the virus, whereas no further changes were noticed in the control cultures.

The Fluid-Flow Theory and Indirect Action of Radiation

In 1937, Dr. Failla published a “fluid-flow” theory of the biologic action of ionizing radiation (1), postulating that ionization increased the osmotic pressure within the cell, causing it to swell. This stress, together with the production of deleterious substances and local damage to membranes, would serve to account for cell death under certain conditions and for cell recovery under others. Failla and Sugiura (2), in 1939, reported findings in irradiated mouse sarcoma 180 tumor cells which tended to support this theory. They tested the postulate further by injecting tumors with distilled water following local treatment with roentgen rays (3) and found greater destruction in these tumors than in those injected with saline. In the ensuing years, the attention of radiobiologists became focused on the nucleus, on cell division, and on chromosome aberrations. This was due, in part, to the resurgent interest in the target theory and the RBE studies demonstrating the importance of specific ionization. Many of the cellular findings appeared to be satisfied by target theory mechanisms. Some of these observations may be mentioned, i.e., dose effect curves based on killing of micro-organisms and on mutation frequency, localized irradiation of chromosomes, lack of effect of temperature and metabolic rate in modifying many radiation effects, lack of effect of protraction or fractionation in altering certain radiation injuries, and the finding of optimal specific ionization for efficiency of radiation production of chromosome aberrations. Interest in chemical aspects was, however, kept alive by Dale's work on enzymes (4), Friedewald and Anderson's studies on rabbit papilloma virus (5), and investigations of radiation inactivation of bacteriophage by Luria and Exner (6). In 1941, a group of us including Dr. Failla carried out a number of experiments in an attempt to explain the finding that sea urchin sperm irradiated in concentrated suspension were relatively radioresistant, but when irradiated in dilute suspension in sea water were very radiosensitive, in respect to viability (7). The results of these experiments enabled us to differentiate between effects produced directly on the cell, nucleus, etc., and those resulting from an indirect action through the medium (8). Our interpretation of the mechanisms was based on the earlier works of Risse (9) and of Fricke (10). We used Fricke's terminology in postulating that x-radiation produced “activated water molecules” in the medium. This finite quantity of activated molecules with a relatively short life could either be dissipated upon the experimental units in the medium or upon other molecules present.

Are Animal Tumor Viruses Always Virus-Like?

Three tumors initiated by well characterized viruses, but in which virus is not detectable by ordinary virological techniques, are discussed. The question of the possible state of the virus within these seemingly non-infectious tumors is considered, largely from the standpoint of findings with the rabbit papilloma virus. This agent in its natural host, the cottontail rabbit, is infective, can be seen as virus bodies with the electron microscope, and can be visualized with fluorescent antibody only in the upper keratinizing cells of individual papillomas. At the growing bases of such papillomas, where neoplasia is in active progress, no infective virus is demonstrable and viral bodies cannot be visualized by either the electron microscope or fluorescent antibody. A hypothesis is presented that rabbit papilloma virus exists in cottontail papillomas in two forms-one, the complete mature virus, composed of nucleic acid and protein, and the other, immature virus, composed of naked viral nucleic acid without its protein coating. The function of the mature papilloma virus is to initiate tumor formation,-that of the immature virus, to maintain neoplasia. In the non-infective domestic rabbit papilloma, the viral nucleic acid and protein fail to combine to form mature infective virus and, as in the cottontail papilloma, neoplasia is maintained by the activity of the viral nucleic acid alone.

A vaccination procedure which increases the frequency of regressions of Shope papillomas of rabbits.

PAPILLOMAS of rabbit skin induced by the virus of Shope are known to undergo complete regression in some animals and to persist indefinitely in others. Carcinomatous change is seen in a high proportion at 6–18 months1. The regression process presents two features of broad significance in the field of tumour immunology: (1) It constitutes rejection of an autologous tumour; (2) The rejection mechanism is effective in some animals and inadequate or absent in others.

Antiviral and Antitumor Immunologic Mechanisms Operative in the Shope Papilloma-Carcinoma System

In 1933 Shope described an infectious papilloma of wild cottontail rabbits. The tumor was regularly transmissible to domestic rabbits on primary inoculation but was not transmissible in indefinite series. He noted that the tumors of 2 animals regressed, whereas in most cases the papillomas persisted indefinitely. During the following 10 years, Rous, Kidd and Beard published extensive studies of these papillomas and of squamous cell carcinomas originating in them. Shope (1937) was the first to note that, although papillomas of domestic rabbits were commonly free of virus as judged by transmission experiments, they nevertheless contained viral antigen as judged by their capacity to stimulate the development of neutralizing antibody and resistance to reinfection following intraperitoneal injection of tissue suspensions. He spoke of “masked” virus and suggested that this might represent either virus rendered inactive by combination with neutralizing substance or by alteration to a non-infective phase. Carcinomas were likewise shown...

INDUCTION OF TUMORS IN DOMESTIC RABBITS WITH NUCLEIC ACID PREPARATIONS FROM PARTIALLY PURIFIED SHOPE PAPILLOMA VIRUS AND FROM EXTRACTS OF THE PAPILLOMAS OF DOMESTIC AND COTTONTAIL RABBITS

A deoxyribonucleic acid preparation which showed infectivity and tumorigenic activity in domestic rabbits was isolated from the papillomatous tissue of wild cottontail rabbits by phenolic deproteinization procedure. The activity of the preparation could be completely abolished by its exposure to a minute amount (0.02 microg/ml) of DNAase. Antisera against Shope papilloma virus did not block the tumorigenic activity of the preparation, and trypsin and chymotrypsin had no effect on it. The extraction with phenol of a partially purified virus preparation also yielded extracts with tumorigenic potency. Extracts obtained from the domestic rabbit papilloma and submitted to phenolic deproteinization also proved infective and tumorigenic in rabbits of this sort, although the level of "tumorigenicity" was much lower than that of the cottontail preparations. Tests for intact virus, carried out with half of the extracts yielded wholly negative findings.

The effect of cervical sympathectomy on experimental papillomas of rabbits' ears.

The Journal of Pathology and BacteriologyVolume 79, Issue 1 p. 151-155 Article The effect of cervical sympathectomy on experimental papillomas of rabbits' ears A. H. Cruickshank, A. H. Cruickshank Department of Pathology, University of LiverpoolSearch for more papers by this authorMargaret M. Summers, Margaret M. Summers Department of Pathology, University of LiverpoolSearch for more papers by this author A. H. Cruickshank, A. H. Cruickshank Department of Pathology, University of LiverpoolSearch for more papers by this authorMargaret M. Summers, Margaret M. Summers Department of Pathology, University of LiverpoolSearch for more papers by this author First published: January 1960 https://doi.org/10.1002/path.1700790119AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Volume79, Issue1January 1960Pages 151-155 RelatedInformation