Retroviral Etiology Research Articles

Гематологічні і молекулярно-генетичні дослідження крові тварин під час випробувань препарату «Лейкозав» проти вірусу лейкозу великої рогатої худоби

This paper presents the results of research in the blood of cattle bovine leukemia. Leukemia cattle - retroviral etiology of tumor disease which has major damage to livestock. Studying the problem of leukemia, scientists have come to a common conclusion - for active struggle must create immunogenic drug against leukemia. The data of experimental work carried out in conditions of epizootic experiments are new and will be able to assist the practical and scientific veterinary experts in carrying out measures to combat this dangerous disease of animals and humans. For this purpose, we developed a new technology for production of inactivated immunogenic preparations, including against bovine leukemia, which the cows tested showed positive results. Employees " State Centre of Innovation Biotechnologies " offered new innovative manufacturing techniques inactivated, immunogenic, harmless drug "Leykozav" which received positive results in the laboratory and epizootic experiments. The drug has not only specific protective properties, but also a positive impact on gender-positive animals (experiments were 50-70% recovery). Objective- to investigate the incubation period of the cow leukemia in terms of epizootic experiment using RID, ELISA and PCR. Influence of "Leykozav" the population of virus in the body and sick cows on hematological parameters of experimental animals. Materials and methods. The study was conducted in disadvantaged on leukemia cattle farm "Danivka" Kozelets district, Chernihiv region, with the number of dairy cattle in 460 cows. Before the experiment, blood and serum of animals examined by RID, ELISA, PCR and hematologic. To study the effect of post-vaccination immunity in a population of virus in the blood of sick cows was formed group (n = 6) who were administered the drug "Leykozav" subcutaneously at a dose of 4 cm 3 twice with an interval of 21 days. Cows in the control group were administered saline (0,9% NaCl) by a similar scheme.Blood samples for the study were collected before the experiment quarterly and nine months (period of observation). Results and discussion. The first symptoms of leukemia among healthy cows (control group), are among the troubled animal herd, appeared after 6 months of the experiment. This is confirmed by real-time PCR.Immunization RID-positive animal drug "Leykozav" impact on reducing the number of copies of DNA provirus leukemia. After the drug decreased the number of copies 7-420 times. The animals in the control group during the period of the experiment marked increase in the number of white blood cells by 34% relative to the norm, whereas other hematological parameters: red blood cells, hemoglobin, hematocrit and platelets remain in the normal range. The use of a series of experimental drug "Leykozav" sick cows leukemia research farm led to minor hematological changes. WBC early experiment was 17,05 ± 3,76, after 9 months. experiment - 15,72 ± 3,37. There is a tendency to decrease. In this case, the concentration of white blood cells decreased by 15.7%. Indicators of red blood cells, hemoglobin, hematocrit and platelet counts in vaccinated animals did not significantly change during the research period and are in the normal range. Thus, the drug does not cause adverse changes in the blood of animals after immunization of prophylactic drug "Leykozav." Conclusions and prospects. 1. In healthy animals that are disadvantaged on leukemia studies, development of infection registered in the 6-9 month studies confirmed that ELISA and PCR. 2. Positive reaction by RID is on the ninth month of the disease, the animal stays in disadvantaged on leukemia herd. 3. Using the quantitative determination of leukemia provirus DNA using polymerase chain reaction not only can detect infected animals in the earliest stages of the disease, but also enables the future and assess the effectiveness of drugs that are recommended for the prevention and treatment of leukemia cattle. 4. Preventive immunization of patients with leukemia drug cow "Leykozav" reduces the number of copies of DNA provirus in blood in 7-420 times. 5. To maintain stability on the welfare of cows in the herd leukemia recommend scheplyuvaty all animals once a year, in the spring or autumn, the drug "Leykozav", following the rules of aseptic and antiseptic.

Koala Retroviruses: Evolution and Disease Dynamics.

A retroviral etiology for malignant neoplasias in koalas has long been suspected. Evidence for retroviral involvement was bolstered in 2000 by the isolation of a koala retrovirus (KoRV), now termed KoRV-A. KoRV-A is an endogenous retrovirus-a retrovirus that infects germ cells-a feature that makes it a permanent resident of the koala genome. KoRV-A lacks the genetic diversity of an exogenous retrovirus, a quality associated with the ability of a retrovirus to cause neoplasias. In 2013, a second KoRV isolate, KoRV-B, was obtained from koalas with lymphomas in the Los Angeles Zoo. Unlike KoRV-A, which is present in the genomes of all koalas in the United States, KoRV-B is restricted in its distribution and is associated with host pathology (neoplastic disease). Here, our current understanding of the evolution of endogenous and exogenous KoRVs, and the relationship between them, is reviewed to build a perspective on the future impact of these viruses on koala sustainability.

Pathology of Tumors in Fish Associated With Retroviruses

Thirteen proliferative diseases in fish have been associated in the literature with 1 or more retroviruses. Typically, these occur as seasonal epizootics affecting farmed and wild fish, and most lesions resolve spontaneously. Spontaneous resolution and lifelong resistance to reinfection are 2 features of some piscine retrovirus-induced tumors that have stimulated research interest in this field. The purpose of this review is to present the reader with the epidemiological and morphological features of proliferative diseases in fish that have been associated with retroviruses by 1 or more of the following methods: detection of C-type retrovirus-like particles or reverse transcriptase activity in tumor tissues; successful tumor transmission trials using well-characterized, tumor-derived, cell-free inocula; or molecular characterization of the virus from spontaneous and experimentally induced tumors. Two of the diseases included in this review, European smelt spawning papillomatosis and bicolor damselfish neurofibromatosis, at one time were attributed to a retroviral etiology, but both are now believed to involve additional viral agents based on more recent investigations. We include the latter 2 entities to update the reader about these developments.

Lack of detection of a putative retrovirus associated with haemic neoplasia in the soft shell clam Mya arenaria

Haemic neoplasia (HN) is a leukemia-like disease that affects at least 20 species of marine bivalves including soft shell clam, Mya arenaria. Since the disease was discovered in 1969, the etiology remains unknown. A retroviral etiology has been suggested based on the detection of reverse transcriptase activity and electron microscopic observation of retroviral-like particles using negative staining. To date, however no virus isolate and no retroviral sequence from HN has been obtained. Moreover, transmission of the disease by cell-free filtrate from affected clams has not been reproduced. In the current study, we reinvestigated the association of HN with a putative retrovirus. Sucrose gradient centrifugation followed by assessment of reverse transcriptase activity, electrophoretic analysis of protein and RNA, and electron microscopic examinations of fractions corresponding to retroviral density were employed. Detection of retroviral pol sequences using degenerate RT-PCR approaches was also attempted. Our results showed visible bands at the expected density of retrovirus in HN-positive and HN-negative clam tissues and both with reverse transcriptase activity. Electron microscopy, RNA analysis, protein analysis, and PCR systems targeting the pol gene of retroviruses did not however provide clear evidence supporting presence of a retrovirus. We point out that the retrovirus etiology of HN of Mya arenaria proposed some 25years ago should be reconsidered in the absence of a virus isolate or virus sequences.

Antileukemia and antitumor effects of the graft-versus-host disease: A new immunovirological approach

In leukemic mice, the native host's explicit and well-defined immune reactions to the leukemia virus (a strong exogenous antigen) and to leukemia cells (pretending in their native hosts to be protected "self" elements) are extinguished and replaced in GvHD (graft-versus-host disease) by those of the immunocompetent donor cells. In many cases, the GvHD-inducer donors display genetically encoded resistance to the leukemia virus. In human patients only antileukemia and anti-tumor cell immune reactions are mobilized; thus, patients are deprived of immune reactions to a strong exogenous antigen (the elusive human leukemia-sarcoma retroviruses). The innate and adaptive immune systems of mice have to sustain the immunosuppressive effects of leukemia-inducing retroviruses. Human patients due to the lack of leukemiainducing retroviral pathogens (if they exist, they have not as yet been discovered), escape such immunological downgrading. After studying leukemogenic retroviruses in murine and feline (and other mammalian) hosts, it is very difficult to dismiss retroviral etiology for human leukemias and sarcomas. Since no characterized and thus recognized leukemogenic-sarcomagenic retroviral agents are being isolated from the vast majority of human leukemias-sarcomas, the treatment for these conditions in mice and in human patients vastly differ. It is immunological and biological modalities (alpha interferons; vaccines; adoptive lymphocyte therapy) that dominate the treatment of murine leukemias, whereas combination chemotherapy remains the main remission-inducing agent in human leukemias-lymphomas and sarcomas (as humanized monoclonal antibodies and immunotoxins move in). Yet, in this apparently different backgrounds in Mus and Homo, GvHD, as a treatment modality, appears to work well in both hosts, by replacing the hosts' anti-leukemia and anti-tumor immune faculties with those of the donor. The clinical application of GvHD in the treatment of human leukemias-lymphomas and malignant solid tumors remains a force worthy of pursuit, refinement and strengthening. Graft engineering and modifications of the inner immunological environment of the recipient host by the activation or administration of tumor memory T cells, selected Treg cells and natural killer (NKT) cell classes and cytokines, and the improved pharmacotherapy of GvHD without reducing its antitumor efficacy, will raise the value of GvHD to the higher ranks of the effective antitumor immunotherapeutical measures. Clinical interventions of HCT/HSCT (hematopoietic cell/stem cell transplants) are now applicable to an extended spectrum of malignant diseases in human patients, being available to elderly patients, who receive non-myeloablative conditioning, are re-enforced by post-transplant donor lymphocyte (NK cell and immune T cell) infusions and post-transplant vaccinations, and the donor cells may derive from engineered grafts, or from cord blood with reduced GvHD, but increased GvL/GvT-inducing capabilities (graft-versus leukemia/tumor). Post-transplant T cell transfusions are possible only if selected leukemia antigen-specific T cell clones are available. In verbatim quotation: "Ultimately, advances in separation of GvT from GvHD will further enhance the potential of allogeneic HCT as a curative treatment for hematological malignancies" (Rezvani, A.R. and Storb, R.F., Journal of Autoimmunity 30:172-179, 2008 (see in the text)). It may be added: for cure, a combination of the GvL/T effects with new targeted therapeutic modalities, as elaborated on in this article, will be necessary.

Investigations on the diagnosis and retroviral aetiology of renal neoplasia in budgerigars (Melopsittacus undulatus)

The high susceptibility of budgerigars (Melopsittacus undulatus) to neoplasia, and specifically renal neoplasia, has often been reported. Further investigations led to a suspicion of a retrovirus as the causative agent for renal neoplasia in budgerigars, but definitive proof has yet to be found. In the present study, 32 budgerigars suspected of having renal neoplasia (based on the clinical presentation) were examined. The objectives were to investigate the use of different diagnostic methods for the ante-mortem diagnosis of this condition and to find more supporting evidence of a retroviral aetiology. The predominant clinical signs observed in budgerigars with renal neoplasia were lameness and absence of deep pain sensation of one leg. Alterations in haematology, plasma chemistry, and urine analyses could not pinpoint the cases of renal neoplasia. Contrast radiography of the intestinal tract proved to be diagnostically more useful compared with plain radiographic studies. Histology confirmed the renal neoplasia as adenocarcinoma. Investigations for virus identification included product-enhanced reverse transcriptase assay and enzyme-linked immunosorbent assay for the detection of avian leucosis virus group-specific antigen. Cell cultures and electron microscopy were performed on a limited number of patients. These investigations could find no presence of an exogenous, replicating retrovirus, neither could viral particles be detected by electron microscopy. Based on the current findings, it can be concluded that there is no evidence of retroviral involvement in the occurrence of renal neoplasia in budgerigars.

Reverse transcriptase activity in tissues of the soft shell clam Mya arenaria affected with haemic neoplasia

Since all retroviruses possess reverse transcriptase (RT) enzyme, reverse transcriptase activity has been the main supportive evidence of retroviral etiology of haemic neoplasia (HN) in soft shell clams, Mya arenaria. The objective of the present study was to search for a putative retrovirus in various tissues of diseased clams following quantification of RT activity (biochemical indicator of retroviral infection). The clams were assessed by flow cytometry (FCM) for diagnosis of HN. RT activity was quantified by TaqMan-product enhanced reverse transcriptase (TM-PERT) assay in four different organs, gonad, gills, digestive gland, and mantle, at various stages of HN. The digestive gland, the organ with the highest RT activity, and haemocytes, the target cell of HN, were assessed by EM for presence of retroviruses. All organs were assessed by histology. The results of this study demonstrated that although all organs of healthy clams have some background RT activity, the activity observed in most of organs of diseased clams was significantly increased ( p < 0.05). An association was observed between the degree of neoplastic cell infiltration and the level of RT activity. Digestive gland showed the highest and most consistent RT activity in both healthy and diseased clams. No evidence for the existence of a retrovirus like particle was found by positive staining EM. The presence of RT activity without indications of retroviral particles in digestive gland and haemocytes suggests a probable endogenous source of RT.

Reverse transcriptase activity associated with haemic neoplasia in the soft-shell clam Mya arenaria

Reverse transcriptase (RT) activity has been reported in bivalves affected by haemic neoplasia (HN). Since all retroviruses have RT, detection of RT activity was regarded as evidence for the retroviral etiology of HN. This study investigates the relationship between RT levels and the progress of HN as indicated by percentages of tetraploid cells in soft-shell clams Mya arenaria. The percentages of tetraploid cells were estimated by flow cytometry, and the RT levels were quantified using TaqMan product-enhanced RT (TM-PERT) assay. Results demonstrated that the amount of RT was positively correlated with the percentage of tetraploid cells circulating in clam haemolymph (R2 = 0.974, p < 0.001). Compared to HN-negative clams (<5% tetraploid cells), 2 stages with significantly elevated levels of RT activity were observed: the first stage at approximately 10 to approximately 20% tetraploid cells, and the second at approximately 30 to approximately 80% tetraploid cells (p < 0.01). These data support the well established fact from mammalian models that transformed cells express high levels of non-telomeric RT. The observed increase in RT levels at approximately 30% tetraploidy coincides with previously reported p53 gene expression. Taken together, this could indicate that using RT levels as an indicator of HN, > or = 30% tetraploidy is the stage at which the disease process undergoes a change, and perhaps becomes irreversible.

Do endogenous retroviruses have etiological implications in inflammatory and degenerative nervous system diseases?

Vertebrates carry large numbers of endogenous retroviruses (ERVs) and related sequences in their genomes. These retroviral elements are inherited as Mendelian traits. Generally, ERVs are defective without the ability of being expressed as viral particles. However, ERV sequences often have a potential for expression of at least some proteins. So far, the possible biological significance of ERVs is not clear. Nonetheless, there are observations suggesting a connection between ERVs and various diseases. This is the case with murine lupus and a spinal cord disease of certain mouse strains. In the present review, we discuss possible mechanisms by which ERVs could contribute to the development of human degenerative and inflammatory nervous system diseases, including direct effects on nervous system cells and immune cells. Interactions between ERVs and infectious viruses are also discussed. Finally, we review a possible retroviral etiology of multiple sclerosis.

Evidence of retroviral etiology for disseminated neoplasia in cockles ( Cerastoderma edule)

Epizootiologic outbreaks of disseminated neoplasia have been reported in association with massive mortalities of various bivalve species. In cockles, Cerastoderma edule, this pathological condition was described in Ireland and France. Since 1997, different populations affected by this pathology have been detected in Galicia (NW Spain). Transmission electron microscopy allowed the visualization of virus-like particles in neoplastic cells, resembling a retrovirus-like agent. To confirm this hypothesis, we used a commercial kit for detection and quantification of reverse transcriptase (RT) activity, based on the use of bromo-deoxyuridine triphosphate (BrdUTP) and a BrdU binding antibody conjugated to alkaline phosphatase. In addition, we developed a product-enhanced RT assay using RNA of hepatitis A virus as a template. These two assays showed positive RT activity in 90.9 and 81.8% of samples, respectively, from cockles displaying disseminated neoplasia as determined by light microscopy. These results strongly support the hypothesis of retroviral etiology for this pathological condition.

Neither an intronic CA repeat within the CD48 gene nor the HERV‐K18 polymorphisms are associated with type 1 diabetes

Type 1 diabetes is an autoimmune heterogeneous disease that is determined by environmental and genetic factors. A possible retroviral etiology has been inferred from the observation that human endogenous retrovirus (HERV)-K18 encoding a superantigen (SAg) has a polymorphism associated with this disease. Type 1 diabetes families from Germany and Belgium were genotyped for the novel HERV-8914 (303 families) and for the known HERV-8594 (284 families) polymorphisms within the SAg-coding region on the HERV-K18. Case-control analysis was performed for the HERV-8914 polymorphism (506 patients) and for the HERV-8594 polymorphism (370 patients) and compared with 350 German controls. Haplotypes were constructed. Additionally, a microsatellite within the CD48 gene was analyzed in German type 1 diabetes families (n=125) as well as in patients (n=375) and in healthy controls (n=350). No association was found for HERV-K18 polymorphisms or the CA repeat within the CD48 gene with type 1 diabetes mellitus either in families or by comparing patients and controls. In conclusion, we cannot confirm a role of HERV-K18 polymorphisms -HERV-8914 and HERV-8594- or of the CD48 CA repeat for type 1 diabetes susceptibility.

MMTV‐like sequences in human breast cancer: a fluorescent PCR/laser microdissection approach

The hypothesis that a retrovirus homologous to the mouse mammary tumour virus (MMTV) is involved in human breast cancer aetiology has fascinated scientists from many years, but it has never been convincingly demonstrated. Renewed interest in this hypothesis developed when an MMTV env gene-like sequence was found in 38% of human breast cancer tissues. Whereas some subsequent studies confirmed these findings, others did not. The main reasons for this discrepancy, among others, are the different sensitivities and technical details of current molecular approaches to the detection of these sequences. This study is an attempt to find sensitive and reproducible conditions capable of detecting MMTV env-like sequence in human samples. To this end, we first developed a fluorescence nested-PCR (FN-PCR) method that was able to detect very low copies of the viral genome, and then screened a panel of 45 frozen breast cancer samples obtained by laser microdissection. The MMTV env gene-like sequence was found in 15 (33%) of the human breast cancers analysed, whereas the same sequence was detectable neither in normal tissues nor in other types of tumour. Sequence analysis revealed 96% homology with the MMTV genome, but no other significant similarities with the human genome. The combined use of frozen material, microdissected cell populations and FN-PCR provides a novel, sensitive, robust, non-radioactive and fast methodology for the molecular detection of human-MTV. This approach might be successfully used in large molecular studies that aim to investigate the hypothesis of a retroviral aetiology of human breast cancer.

The discovery of the first human retrovirus: HTLV-1 and HTLV-2

I describe here the history leading up to and including my laboratory's discovery of the first human retrovirus, HTLV-I, and its close relative, HTLV-II. My efforts were inspired by early work showing a retroviral etiology for leukemias in various animals, including non-human primates. My two main approaches were to develop criteria for and methods for detection of viral reverse transcriptase and to identify growth factors that could support the growth of hematopoietic cells. These efforts finally yielded success following the discovery of IL-2 and its use to culture adult T cell lymphoma/leukemia cells.

Apocalypsal versus Apocryphal: The Role of Retroviruses in Primary Biliary Cirrhosis

The etiology of primary biliary cirrhosis (PBC), much like that of other autoimmune diseases, remains enigmatic. In the case of PBC, several candidates have been proposed, including bacteria, chemicals, and retroviruses. The support for a retroviral etiology has led to a pilot therapeutical interventional program. However, there is limited objective data which can be used to support such a thesis. Until reproducible and mechanistically sound data can be offered, we suggest that pharmaceutical trials are unrealistic and should be discouraged.

Lack of immunological or molecular evidence for a role of mouse mammary tumor retrovirus in primary biliary cirrhosis

Background & Aims: Recent observations, including a pilot clinical trial, have suggested that a human mouse mammary tumor virus (MMTV) causes primary biliary cirrhosis (PBC). We attempted to confirm such data. Methods: We obtained sera from 101 patients (53 with PBC and 48 controls), fixed liver sections from 10 patients (8 PBC and 2 controls), fresh liver specimens (6 PBC and 6 controls), and fresh peripheral blood lymphocytes (PBLs) (10 PBC and 10 controls). We studied sera for reactivities against 3 different strains of MMTV virions, MMTV(C3H), MMTV(FM), and MMTV(LA), including goat polyclonal antibodies against MMTV virions, gp52, and p27 as positive controls. We stained liver specimens using polyclonal antibodies against MMTV and gp52 and further examined tissue samples and PBLs for specific MMTV genome sequences. Results: By Western blot analysis, no detectable reactivity in any of the PBC sera against any of the 3 MMTV strains or MMTV gp52 or p27 was observed. However, viral proteins were recognized by our control positive polyclonal antibodies. We note that 13%–60% of PBC sera presented low reactivity against 2 proteins of approximately 57 and 74 kilodaltons. Such reactivity is related to the trace amounts of mitochondrial antigens in the virus preparations derived from murine mammary tumor tissue. No detectable immunohistochemical or molecular evidence for MMTV was found in the liver specimens or PBLs. Conclusions: We were unable to recapitulate the data on this specific retroviral etiology of PBC and suggest that such data could be the result of contamination.

Transient Reversal of HIV-Associated Motor Neuron Disease Following the Introduction of Highly Active Antiretroviral Therapy

Neurological diseases occur frequently in patients with human immunodeficiency virus (HIV) infection, and include a variety of neuromuscular disorders. On the other hand, only a few cases of motor neuron disease (MND) have been reported to date in HIV-positive patients, even though this neurological complication occurs with a 27-fold greater frequency in these subjects compared with the general population. A retroviral etiology for MND has long been hypothesized, and epidemiological and experimental data suggest a pathogenetic link between HIV infection and MND, because retroviral infections may cause motor neuron damage in both laboratory animals and humans, as a result of various pathways. Furthermore, the introduction of potent, protease inhibitor-based antiretroviral combinations has had a great impact on the natural history of HIV disease and produced a dramatic improvement in some patients with HIV-associated MND, but optimal treatment for this progressive neurological complication has not been well defined. A case of MND in a male HIV-infected patient with significant but transient reversal of neurological symptoms after the use of protease inhibitor-containing antiretroviral regimen is described.

Gene expression of novel retro virus associated with human acute muloid leukemia

Objective: To explore the potentiality of retroviral etiology in human acute myeloid leukemia(AML). Methods: The expression of clone 6#11 in leukemic cell samples from 19 AML cases and peripheral blood mononuclear cells (PBMNCs) from 20 controls was studied by means of Northern blot and reversal transcription polymerase chain reaction (RT-PCR). Results: Northern blot and RT-PCR analyses showed that the expression level of clone 6#11 was significantly higher in AML patients than that in control. Conclusion: Northern blot and RT-PCR analyses revealed that the expression of novel retrovirus were associated with acute myeloid leukemia.

Lymphosarcoma in Hatchery-Reared Yearling Tiger Muskellunge

Yearling tiger muskellunge (northern pike Esox lucius × muskellunge E. masquinongy) being cultured within the Colorado Division of Wildlife's fish hatchery system were found to have external lesions that were grossly and microscopically consistent with descriptions of esocid lymphosarcoma. This neoplasia has been described as a tumor of adult northern pike and muskellunge; a retroviral etiology has been proposed for it. However, esocid lymphosarcoma has not previously been reported in tiger muskellunge. Owing to concerns about the potentially infectious nature of the condition in a hatchery environment, an experiment was conducted to determine whether the lesion could be transmitted to naive young-of-the-year tiger muskellunge in the laboratory by means of cell-free filtrates. At 32 weeks postchallenge, grossly visible lesions were observed on the challenged fish. Histological evaluation of these lesions confirmed that they were esocid lymphosarcoma. We believe that this is the first report of the natural occurrence of this disease in tiger muskellunge as well as in any esocid that was not an adult.

The genome of Rickettsia prowazekii, the causative agent of typhus

Since the discovery in the early 1980s that retroviruses arc pathogenic to man, the mouse mammary tumor viruses (MMTVs) received great attention. Studies of MMTVs allowed considerable insights into the mechanisms at work in breast tumorigenesis. MMTVs arc essentially insertional mutagenes Numerous oncogenes have been found altered by MMTVs, either specific for MMTVs or not. However, despite considerable attempts, the involvement of MMTVs in human breast cancer remains questionable. Yet a retroviral etiology of human breast cancer cannot be discarded since retroviruses are good candidates to play a role in diseases which, like human breast cancer, appear either as sporadic or inherited. Due to their replication cycle, retroviruses can be propagated not only as infectious agents able to freely infect host cells, but also as cellular genes which car be passed on to progeny. It is suggested here to search for a new human retrovirus in sporadic breast cancer, using the techniques which led to the isolation of human T-cell leukemia virus-1 (HTLV-1). Indeed, finding an infectious retrovirus in sporadic cases could lead, via the c-DNA probes derived from it, to testing the hypothesis that the inherited form of human breast cancer may result from the action of retroviral genes integrated in the germ line.

Possible retroviral origin of prion disease: could prion disease be reconsidered as a preleukemia syndrome?

A retroviral etiology might explain why amyloid plaque and/or spongiosis are or are not associated with neuronal death in prion diseases. While retroviral genes themselves may be responsible for neuronal death, a retrovirus may also cause mutations in cellular genes. Hence, the prion gene may be altered by a retrovirus in the same way as a cellular proto-oncogene is altered to produce an oncogene, either by transduction or by integration of the provirus in its vicinity. In both cases, the resulting abnormal prion protein, acting as a catalyst, may induce the formation of amyloid plaques. In addition, a wild type retrovirus may recombine to the vesicular stomatitis virus (VSV) to give rise to a pseudotyped retrovirus able to induce spongiosis. It is reported here that in scrapie, a blood monocytoid cell proliferates in vitro. If confirmed in other species, this raises the question of the potential link between prion disease and leukemia. Indeed neurovirulent strains of murine leukemia virus, a slow acting retrovirus, are known to induce spongiform encephalopathies. A preliminary attempt to purify reverse transcriptase by chromatography, using the classical protocol, failed because of the presence of a prion-like protein secreted by the blood mononuclear cells which stuck to the phosphocellulose column. Therefore, if a retrovirus is present in prion diseases, it would be evidenced only in animals developing the disease in the absence of prion protein. From this point of view, mice obtained in 1997 by the group of D. Dormont in France, offer a unique opportunity to test the retroviral hypothesis.