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Sepsis remains the leading cause of death in critically ill patients. One of the primary organs affected by sepsis is the lung, presenting as the Acute Respiratory Distress Syndrome (ARDS). Organ damage in sepsis involves an alteration in gene expression, making gene transfer a potential therapeutic modality. This work examines the feasibility of applying simian virus 40 (SV40) vectors for pulmonary gene therapy.
Malignant pleural mesothelioma (MPM) is associated with a history of heavy, long-term exposure to asbestos. However, MPM may also be associated with simian virus 40 (SV40), a polyomavirus. The association between SV40 and MPM remains unclear. The present study was conducted in order to investigate the proportion of SV40 presence in the histological specimens of Vietnamese patients with MPM. Histological specimens were obtained from 45 patients (19 men and 26 women) with MPM at the Pham Ngoc Thach Hospital in Ho Chi Minh City, Vietnam. The specimens were processed and examined in order to detect the presence of the SV40 large T antigen (SV40 Tag) expression using immunohistochemistry. Of the 45 patients, 23 (51%) were epithelioid, 7 (16%) were biphasic, 6 (13%) were sarcomatoid, 4 (9%) were desmoplastic, 4 (9%) were well-differentiated papillary and 1 (2%) was the anaplastic subtype. In total, 9/45 patients (20%) demonstrated SV40 Tag expression. The proportion of patients that demonstrated SV40 Tag expression was not significantly different between the epithelioid subtype and the other subtypes (22 vs. 18%; P=1.000) or between the patients with stage IV disease and other stages (20 vs. 20%; P=1.000). The median survival time was not significantly different between the patients with or without SV40 Tag expression (196 vs. 236 days, P=0.8949). In summary, a 5th of the Vietnamese patients with MPM were associated with infection with SV40. SV40 may be a potential cause of MPM in Vietnam and this potential association requires additional studies.
Simian virus 40 (SV40) large T antigen (TAg) is a multifunctional oncoprotein essential for productive viral infection and for cellular transformation. We have used microarray analysis to examine the global changes in cellular gene expression induced by wild-type T antigen (TAg(wt)) and TAg-mutants in mouse embryo fibroblasts (MEFs). The expression profile of approximately 800 cellular genes was altered by TAg(wt) and a truncated TAg (TAg(N136)), including many genes that influence cell cycle, DNA-replication, transcription, chromatin structure and DNA repair. Unexpectedly, we found a significant number of immune response genes upregulated by TAg(wt) including many interferon-stimulated genes (ISGs) such as ISG56, OAS, Rsad2, Ifi27 and Mx1. Additionally, we also observed activation of STAT1 by TAg(wt). Our genetic studies using several TAg-mutants reveal an unexplored function of TAg and indicate that the LXCXE motif and p53 binding are required for the upregulation of ISGs.
Simian virus 40 (SV40), a polyomavirus, was discovered as a contaminant of a human polio vaccine in the 1960s. It is known that malignant mesothelioma (MM) is associated with SV40, and that the virus works as a cofactor to the carcinogenetic effects of asbestos. However, the reports about the correlation between SV40 and MM have not been consistent. The purpose of this study is to identify SV40 in MM tissue in Korea through detection of SV40 protein and DNA.
We constructed simian virus 40 (SV40)/polyomavirus recombinants by replacing in SV40 the T antigen coding region with polyoma early region sequences, either cDNAs encoding small, middle or large T antigen or the wild-type sequence coding all three proteins. The recombinants maintained the SV40 late region and origin of replication and were propagated in COS cells yielding recombinant virus preparations with titers of 10(6)-10(7) infectious particles per milliliter. These viruses were characterized in productive infections of COS cells by analyzing early and late mRNA levels and by following synthesis of polyoma early proteins. In the absence of viral DNA replication, i.e. in infected monkey or mouse cells, expression of the polyoma T antigens was weak. Further experiments indicated that this was mostly due to high genomic instability during amplification, to lower levels of cDNA transcripts as compared to spliced mRNA, and possibly also to lower infectivity of the recombinant virions. It remains to be determined, whether these handicaps are unique to SV40/polyoma recombinants or whether SV40 is in general inadequate as a viral vector.
SV40 transforms cells through the action of two oncoproteins, large T antigen and small t antigen. Small t antigen targets phosphatase PP2A, while large T antigen stimulates cell proliferation and survival by action on multiple proteins, including the tumor suppressors Rb and p53. Large T antigen also binds components of the transcription initiation complex and several transcription factors. We examined global gene expression in SV40-transformed mouse embryo fibroblasts, and in enterocytes obtained from transgenic mice. SV40 transformation alters the expression of approximately 800 cellular genes in both systems. Much of this regulation is observed in both MEFs and enterocytes and is consistent with T antigen action on the Rb-E2F pathway. However, the regulation of many genes is cell-type specific, suggesting that unique signaling pathways are activated in different cell types upon transformation, and that the consequences of SV40 transformation depends on the type of cell targeted.
Signaling pathways known to have components with mutations in human medulloblastoma include sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor. Microarray analysis was applied to examine the gene expression changes in medulloblastomas of pTet-on/pTRE-SV40Tag transgenic mice. Altogether, 14 112 genes were detectable, including 152 genes with significantly different expression levels. These genes were associated with immunity, the cell cycle, signal transduction, cytoskeleton and metabolism. To further confirm the microarray data, real-time polymerase chain reactions were used to examine the expression changes of genes related to sonic hedgehog, Wnt/beta-catenin and insulin-like growth factor signal pathways. Immunohistochemistry detected insulin receptor substrate-1 in the nuclei of brain tumor tissue cells from pTet-on/pTRE-SV40Tag transgenic mice, suggesting that SV40 large T antigen may activate the insulin-like growth factor signal pathway to promote tumorigenesis.
We observed six major tryptic phosphopeptides in p53 from simian virus 40-transformed and normal NIH 3T3 cells. Analyses of the phosphopeptides indicated that serines 37, 310 and/or 312, 389 and one or more of serines 7, 9, 12, 18, and 23 were phosphorylated. Phosphorylation of serines 310 and/or 312 was twofold higher in the simian virus 40-transformed cells as compared with that in normal NIH 3T3 cells.
Dendritic cells (DC) are the initiators and modulators of the immune responses. Some species of pathogenic microorganisms have developed immune evasion strategies by controlling antigen presentation function of DC. Simian virus 40 (SV40) is a DNA tumor virus of rhesus monkey origin. It can induce cell transformation and tumorigenesis in many vertebrate species, but often causes no visible effects and persists as a latent infection in rhesus monkeys under natural conditions. To investigate the interaction between SV40 and rhesus monkey DC, rhesus monkey peripheral blood monocyte-derived DC were induced using recombinant human Interleukin-4 (rhIL-4) and infective SV40, the phenotype and function of DC-specific intracellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN)(+) DC were analyzed by flow cytometry (FCM) and mixed lymphocyte reaction (MLR). Results showed that SV40 can down-regulate the expression of CD83 and CD86 on DC and impair DC-induced activation of T cell proliferation. These findings suggest that SV40 might also cause immune suppression by influencing differentiation and maturation of DC.
Polyomavirus simian virus 40 (SV40) sequences have been detected in various human specimens and SV40 antibodies have been found in human sera from both healthy individuals and cancer patients. This study analyzed serum samples from healthy pregnant women as well as cord blood samples to determine the prevalence of SV40 antibodies in pregnancy.
At present Simian virus 40 (SV40) infection in humans appears to be transmitted independently from early contaminated vaccines. In order to test the spread of SV40 infection in children, an immunologic assay employing specific SV40 synthetic peptides corresponding to its viral protein (VP) antigens was employed to estimate the seroprevalence of this polyomavirus in Italian infants and adolescents. Serum samples from 328 children and adolescents, up to 17 years, were investigated. Serum antibodies against SV40 VPs were detected by indirect enzyme-linked immunosorbent assays. The seroprevalence of this polyomavirus was calculated after stratifying the subjects by age. Anti-viral capsid protein 1-2-3 SV40 IgG antibodies were detected in 16% of the study participants. The prevalence of antibodies against SV40 VPs tended to increase with age in children, up to 10 year old (21%). Then, in the cohort of individuals aged 11-17 years, the prevalence decreased (16%). A higher prevalence rate (23%) of SV40 VP antibodies was detected in the cohorts of 1-3 year and 7-10 year old children, than in children and adolescents of the other age groups. This age corresponds to children starting nursery and primary school, respectively, in Italy. IgM antibodies against SV40 VP mimotopes were detected in 6-8 month old children suggesting that SV40 seroconversion can occur early in life. SV40 VP antibodies are present at low prevalence in Italian children (16%), suggesting that SV40 infection, although acquired early in life, probably through different routes, is not widespread. The low SV40 seroprevalence suggests that SV40 is less transmissible than other common polyomaviruses, such as BKV and JCV. Alternatively, our immunologic data could be due to another, as yet undiscovered, human polyomavirus closely related to SV40.
Human osteosarcoma (OS) is a rare human cancer, mostly occurring in children and adolescents. Simian virus 40 (SV40 = Macaca mulatta polyomavirus 1) sequences have been detected in different human cancers, including osteosarcoma. SV40 is an oncogenic virus in vivo, whereas it transforms different kinds of mammalian cells, as well as distinct human cell types. SV40 injected in rodents induces tumors of different histotypes, such as bone and brain tumors. Herein, the association between OS and SV40 large T antigen (Tag) was studied by employing indirect ELISAs using synthetic peptides that mimic different epitopes of the SV40 Tag, the viral oncoprotein. Indirect ELISAs were used to detect serum IgG antibodies against this oncogenic virus in samples from OS patients. Controls were sera from healthy subjects (HS) and oncological patients affect by breast cancer (BC), which is not associated with SV40. It turned out that sera of OS patients had a higher prevalence of SV40 Tag antibodies, 35%, compared to HS, 20% and BC, 19%, respectively. The different prevalence of SV40 Tag antibodies revealed in OS vs. HS and vs. BC is statistically significant with P < 0.05 and P < 0.01, respectively. Our immunological data indicate a significantly higher prevalence of antibodies against SV40 Tag epitopes in serum samples from OS patients compared to HS and BC, the controls. These results suggest an association between OS and SV40 Tag, indicating that this oncogenic virus may be a cofactor in OS development.
Promyelocytic nuclear bodies (PML-NBs) are distinct nuclear structures that are involved in apoptosis, differentiation, transcriptional regulation and DNA damage response. These bodies have also been shown to associate with nuclear sites of viral DNA replication. In the present study, we used BrdU pulse labeling to demonstrate that PML-NBs accumulate newly synthesized DNA in cells infected by the polyomaviruses simian virus 40 (SV40) or polyomavirus BK (BKV). Sequestration of DNA molecules in these structures depended on active viral DNA replication, and was observed exclusively in cells that contained prominent viral replication domains. Furthermore, a significant portion of the accumulated DNA was found to be single-stranded, indicating that the sequestered DNA had been subjected to processing by nuclease or DNA unwinding activities. siRNA-mediated suppression of the PML protein prevented the recruitment of single-stranded DNA into nuclear foci, but did not significantly affect the overall efficiency of viral DNA replication. These results indicate a role of PML and PML-NBs in post-replication DNA processing, and suggest that PML-NBs become linked to sites of viral DNA synthesis due to a role of these structures in DNA metabolism.
Simian Virus 40 (SV40) has been shown to enter host cells by caveolar endocytosis followed by transport via caveosomes to the endoplasmic reticulum (ER). Using a caveolin-1 (cav-1)-deficient cell line (human hepatoma 7) and embryonic fibroblasts from a cav-1 knockout mouse, we found that in the absence of caveolae, but also in wild-type embryonic fibroblasts, the virus exploits an alternative, cav-1-independent pathway. Internalization was rapid (t1/2 = 20 min) and cholesterol and tyrosine kinase dependent but independent of clathrin, dynamin II, and ARF6. The viruses were internalized in small, tight-fitting vesicles and transported to membrane-bounded, pH-neutral organelles similar to caveosomes but devoid of cav-1 and -2. The viruses were next transferred by microtubule-dependent vesicular transport to the ER, a step that was required for infectivity. Our results revealed the existence of a virus-activated endocytic pathway from the plasma membrane to the ER that involves neither clathrin nor caveolae and that can be activated also in the presence of cav-1.
The large T antigen (T-ag) protein binds to and activates DNA replication from the origin of DNA replication (ori) in simian virus 40 (SV40). Here, we determined the crystal structures of the T-ag origin-binding domain (OBD) in apo form, and bound to either a 17 bp palindrome (sites 1 and 3) or a 23 bp ori DNA palindrome comprising all four GAGGC binding sites for OBD. The T-ag OBDs were shown to interact with the DNA through a loop comprising Ser147-Thr155 (A1 loop), a combination of a DNA-binding helix and loop (His203-Asn210), and Asn227. The A1 loop traveled back-and-forth along the major groove and accounted for most of the sequence-determining contacts with the DNA. Unexpectedly, in both T-ag-DNA structures, the T-ag OBDs bound DNA independently and did not make direct protein-protein contacts. The T-ag OBD was also captured bound to a non-consensus site ATGGC even in the presence of its canonical site GAGGC. Our observations taken together with the known biochemical and structural features of the T-ag-origin interaction suggest a model for origin unwinding.
The effects of malondialdehyde (MDA), a product of oxidative stress, on normal lung fibroblast cells (MRC5) and transformed cells (MRC5 SV2) showed differing responses between the two cell lines. MRC5 cells showed lower viability at low MDA concentrations (<250 μM) but had better viability at higher concentrations than the transformed cells. Both cell lines showed an increase in the number of micronuclei, nuclear size and a relocation of p53 to the nucleus with increasing MDA. The expression of p53 was higher in the MRC5 cells at 24 h; 2-8 fold induction vs 1-2.5 fold in the MRC5 SV2 cells, but reduced to almost zero at 48 h in the MRC5 cells. Mutation sequencing of the PCR products of a 689 bp region (residues 4640-5328) of the TP53 gene revealed MRC5 had more mutations than MRC5 SV2 cells (n = 21 and 11 respectively) and that they were predominantly insertions (MRC5 81%, MRC5 SV2 100%). A common mutation was observed in both cell lines; a G insertion at residue 4724 (n = 7) which could prove to be a mutational hotspot. These results indicate that the transformed cells are slower to respond to oxidative stress and/or mutagenic compounds. The mutation spectrum of predominantly frameshift mutations (insertions) suggests that oxidative stress plays a minimal role in smoking related lung cancer, but could be of greater importance to other lung diseases and cancer caused by exposures such as passive smokers, passive vapers and atmospheric pollutants.
A hybrid gene comprising the bovine thyroglobulin gene promoter and the coding region for the simian virus-40 large T- and small t-antigens was used to generate 30 transgenic mice by microinjection into the pronuclei of single cell embryos. All animals except three developed, as single primitive pathology, a dramatic enlargement of the thyroid gland. Compression of trachea and esophagus, accompanied by dyspnea, inspiratory stridor, and dysphagia, led to a progressive cachexia and premature death attributed to respiratory failure. Despite the large thyroid volume, T4 levels were abnormally low, and the progression of the syndrome could be delayed by a substitutive treatment with thyroid hormones. The rapid evolution of the disease, leading to the death of most founder transgenic animals before the breeding age, prevented transmission of the transgene to their offspring. Only two transgenic lines are presently surviving. Immunohistochemical analysis of the tissues revealed a specific expression of the simian virus-40 antigens in the thyroid cells. Hyperplasia was already obvious at birth. Older animals displayed moderately to poorly differentiated thyroid adenocarcinomas. Electron microscopy revealed, however, the persistence of cell polarity and the presence of microfollicles between the densely packed cells. Cell lines derived from these large T-expressing thyroids were shown to have lost expression of both thyroglobulin and thyroperoxidase, while expressing low levels of TSH receptors. These transgenic mice could constitute an interesting model of aggressive adenocarcinoma, sharing phenotypical similarities with the anaplastic type of human thyroid tumors.
Simian virus 40 (SV40), a polyomavirus that has served as an important model to understand many aspects of biology, induces dramatic cytoplasmic vacuolization late during productive infection of monkey host cells. Although this activity led to the discovery of the virus in 1960, the mechanism of vacuolization is still not known. Pentamers of the major SV40 capsid protein VP1 bind to the ganglioside GM1, which serves as the cellular receptor for the virus. In this report, we show that binding of VP1 to cell surface GM1 plays a key role in SV40 infection-induced vacuolization. We previously showed that SV40 VP1 mutants defective for GM1 binding fail to induce vacuolization, even though they replicate efficiently. Here, we show that interfering with GM1-VP1 binding by knockdown of GM1 after infection is established abrogates vacuolization by wild-type SV40. Vacuole formation during permissive infection requires efficient virus release, and conditioned medium harvested late during SV40 infection rapidly induces vacuoles in a VP1- and GM1-dependent fashion. Furthermore, vacuolization can also be induced by a nonreplicating SV40 pseudovirus in a GM1-dependent manner, and a mutation in BK pseudovirus VP1 that generates GM1 binding confers vacuole-inducing activity. Vacuolization can also be triggered by purified pentamers of wild-type SV40 VP1, but not by GM1 binding-defective pentamers or by intracellular expression of VP1. These results demonstrate that SV40 infection-induced vacuolization is caused by the binding of released progeny viruses to GM1, thereby identifying the molecular trigger for the activity that led to the discovery of SV40.
Simian virus 40 large T-antigen (SV40 LT-Ag) is a 708 amino acid nuclear phosphoprotein. Among many functions of LT-Ag is its ability to perform as an ATPase-helicase, catalyzing the unwinding of viral genome during replication. The LT-Ag has been employed in the studies of helicase structure and function, and has served as a model helicase for the screening of antiviral drugs that target viral helicase. In this study, using in vitro enzyme assays and in silico computer modeling, we screened a batch of 18 fluoroquinolones to assess their potential as antivirals by virtue of their inhibition of the LT-Ag helicase. We found all fluoroquinolones to be inhibitory to the helicase activity of LT-Ag. In our docking analysis, most of these tested drugs showed similarity in their interactions with LT-Ag. Our study shows the potential of fluoroquinolones as antiviral drugs and of SV40 LT-Ag as a model protein for screening drugs against viral helicases.
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