Simian Sarcoma Virus Research Articles

Viral infection and glioma: a meta-analysis of prognosis

BackgroundGlioma is the most common primary brain tumor, occurring due to the carcinogenesis of glial cells in the brain and spinal cord. Many aspects of the mechanism of its tumorigenesis remain unknown. The relationship between viral infection and glioma is one of the most important research aspects in this field. Currently, there is a lack of systematic reviews and meta-analyses to evaluate the effect of viral infection on the prognosis of glioma patients. The purpose of this study was to evaluate the relationship between viral infection and the prognosis of glioma patients, aimed at evaluating the prognostic value of the detection of viral infection.MethodsThrough careful and comprehensive retrieval of results from the PubMed, Embase, and Cochrane databases, eligible articles were selected strictly according to the inclusion and exclusion criteria. The regional sources, detection methods, detection indicators, patient survival, and other data from the samples in the papers were extracted, and the integrated analysis was conducted using Stata 15.1. We conducted a subgroup analysis of the relationship between the degree of infection and prognosis in cytomegalovirus (CMV) patients.ResultsA total of 11 studies were included in the analysis. Among them, 7 studies involved the relationship between CMV infection and the prognosis of patients with glioma, 2 studies involved human papillomavirus (HPV), 2 studies involved human herpesvirus-6 (HHV-6), and one study involved simian virus 40 (SV40), woolly monkey sarcoma virus (WMSV) and human endogenous retrovirus K113 (HERV-K113). In the CMV study, the pooled Hazard ratio (HR) of Overall survival (OS) was 1.024 (CI: 0.698–1.501), with a P value of 0.905. The pooled HR of Progression free survival (PFS) was 1.067 (CI: 0.770–1.478), with a P value of 0.697. The pooled HR value of low-degree infection versus high-degree infection was 1.476 (CI: 0.799–2.727), with a P value of 0.213. In the HPV study, the pooled HR of OS was 1.467 (CI: 0.552–3.901), with a P value of 0.443.ConclusionCMV infection has no significant effect on the prognosis of glioma patients. Using the IEA as the detection index, the degree of CMV infection was found to have a significant impact on the prognosis of glioma patients; it was not found to possess a significant prognostic value after the integration of different indicators. Neither HPV nor HHV-6 infection has a significant effect on the prognosis of glioma patients. SV40 and WMSV infection are associated with poor prognosis in patients with low-grade glioma.Trial RegistrationThis meta-analysis registered in https://www.crd.york.ac.uk/PROSPERO/, PROSPERO ID: CRD42019127648.

Herceptin: A First Assault on Oncogenes that Launched a Revolution

This year's Lasker Clinical Research Award honors H. Michael Shepard, Dennis J. Slamon, and Axel Ullrich for their invention of Herceptin, the first monoclonal antibody that blocks a cancer-causing protein, and for its development as a life-saving therapy for women with breast cancer.

The Landscape of Viral Expression Reveals Clinically Relevant Viruses with Potential Capability of Promoting Malignancy in Lower-Grade Glioma.

Purpose: RNA sequencing (RNA-seq) has recently proved to be effective for revealing novel virus-tumor associations. To get a thorough investigation of virus-glioma associations, we screened viruses in gliomas with RNA-seq data from the Chinese Glioma Genome Atlas project.Experimental Design: In total, 325 samples were enrolled into this study. Reads that failed to map to the human genome were aligned to viral genomes and screened for potential virus-derived transcripts. For quantification, VPKM was calculated according to mapped reads weighted by genome sizes and sequencing depth.Results: We observed that viruses tended to concertedly express in a certain subgroup of patients. Survival analysis revealed that individuals who were infected with Simian virus 40 (SV40) or woolly monkey sarcoma virus (WMSV) had a significantly shorter overall survival than those uninfected. A multivariate Cox proportional hazards model, taking clinical and molecular factors into account, was applied to assess the prognostic value of SV40 and WMSV. Both SV40 and WMSV were independent prognostic factors for predicting patient's survival in lower-grade gliomas. Subsequent gene analysis demonstrated that SV40 was correlated with regulation of transcription, whereas WMSV was correlated with cell-cycle phase, which indicated frequent proliferation of tumor cells.Conclusions: RNA-seq was sufficient to identify virus infection in glioma samples. SV40 and WMSV were identified to be prognostic markers for patients with lower-grade gliomas and showed potential values for targeting therapy. Clin Cancer Res; 23(9); 2177-85. ©2016 AACR.

Bengt Westermark and our current understanding of tumor pathogenesis

Bengt Westermark and our current understanding of tumor pathogenesis

Identification of Amino Acids in HIV-1 and Avian Sarcoma Virus Integrase Subsites Required for Specific Recognition of the Long Terminal Repeat Ends

A tetramer model for HIV-1 integrase (IN) with DNA representing 20 bp of the U3 and U5 long terminal repeats (LTR) termini was assembled using structural and biochemical data and molecular dynamics simulations. It predicted amino acid residues on the enzyme surface that can interact with the LTR termini. A separate structural alignment of HIV-1, simian sarcoma virus (SIV), and avian sarcoma virus (ASV) INs predicted which of these residues were unique. To determine whether these residues were responsible for specific recognition of the LTR termini, the amino acids from ASV IN were substituted into the structurally equivalent positions of HIV-1 IN, and the ability of the chimeras to 3 ' process U5 HIV-1 or ASV duplex oligos was determined. This analysis demonstrated that there are multiple amino acid contacts with the LTRs and that substitution of ASV IN amino acids at many of the analogous positions in HIV-1 IN conferred partial ability to cleave ASV substrates with a concomitant loss in the ability to cleave the homologous HIV-1 substrate. HIV-1 IN residues that changed specificity include Val(72), Ser(153), Lys(160)-Ile(161), Gly(163)-Val(165), and His(171)-Leu(172). Because a chimera that combines several of these substitutions showed a specificity of cleavage of the U5 ASV substrate closer to wild type ASV IN compared with chimeras with individual amino acid substitutions, it appears that the sum of the IN interactions with the LTRs determines the specificity. Finally, residues Ser(153) and Val(72) in HIV-1 IN are among those that change in enzymes that develop resistance to naphthyridine carboxamide- and diketo acid-related inhibitors in cells. Thus, amino acid residues involved in recognition of the LTRs are among these positions that change in development of drug resistance.

Regulatory mechanisms for the expression and activity of platelet-derived growth factor receptor.

PDGF is one of the most potent serum mitogens, and the signalling mechanism by way of its receptor tyrosine-kinase has been extensively studied since its first purification in 1979. The identification of homology between the simian sarcoma virus oncogene, v-sis, and the B-chain of PDGF, as well as the frequent over-expression of both the ligands and receptors in various tumours and stroma led to the proposal of the PDGF-mediated autocrine and paracrine hypothesis. Consistent with the important roles of PDGF in the growth and survival of cells, the expression and activity of PDGF receptors are tightly controlled by both positive and negative feedback mechanisms at different levels. The deregulation of the control system can result in serious pathological conditions such as chronic inflammation and tumours. Understanding the molecular mechanisms for the regulatory system and the signalling pathway of PDGF is essential in order to find effective therapies in the diseases where PDGF is involved.

Regulatory mechanisms for the expression and activity of platelet-derived growth factor receptor.

PDGF is one of the most potent serum mitogens, and the signalling mechanism by way of its receptor tyrosine-kinase has been extensively studied since its first purification in 1979. The identification of homology between the simian sarcoma virus oncogene, v-sis, and the B-chain of PDGF, as well as the frequent over-expression of both the ligands and receptors in various tumours and stroma led to the proposal of the PDGF-mediated autocrine and paracrine hypothesis. Consistent with the important roles of PDGF in the growth and survival of cells, the expression and activity of PDGF receptors are tightly controlled by both positive and negative feedback mechanisms at different levels. The deregulation of the control system can result in serious pathological conditions such as chronic inflammation and tumours. Understanding the molecular mechanisms for the regulatory system and the signalling pathway of PDGF is essential in order to find effective therapies in the diseases where PDGF is involved.

Simian retrovirus infections: potential confounding variables in primate toxicology studies.

Various species of nonhuman primates are natural hosts for 6 exogenous retroviruses, including gibbon-ape leukemia virus (GaLV), simian sarcoma virus, simian T-lymphotropic virus (STLV), simian immunodeficiency virus (SIV), simian type D retrovirus (SRV), and simian foamy virus (SFV). These viruses establish persistent infections with a broad spectrum of pathogenic potential, ranging from highly pathogenic to nonpathogenic, depending on various host, virus, and environmental factors. Latent or subclinical infections are common, and various procedures associated with experimental protocols may lead to virus reactivation and disease. Adverse effects on toxicologic research by undetected retroviral infections can occur in several ways, including loss of experimental subjects (and statistical power) due to increased morbidity and mortality. In addition, results may be confounded by virus-induced clinical abnormalities, histologic lesions, alteration of physiologic parameters and responses, and interference with in vitro assays and/or destruction of primary cell cultures. Key clinical and epidemiological features of several important retroviruses are reviewed, with emphasis on viruses infecting species of macaques most commonly used as research subjects in primate toxicology studies. Examples of actual and potential confounding of toxicologic studies by retroviruses are discussed, including altered cytokine profiles in healthy STLV carriers, and clinical and pathological abnormalities induced by SRV infection. Adequate prestudy viral screening is critical to exclude retrovirus-infected primates from toxicologic research protocols and prevent potential confounding of research results.

In vitro triplex formation and functional analysis of TFOs designed against human c-sis/PDGF-B proto-oncogene

PDGF (platelet derived growth factor) has been shown to play an important role in tumorigenesis, tumor growth, atherosclerosis and inflammation and other various pathologic settings. PDGF-B chain gene is 92% homologous to v-sis oncogene of the simian sarcoma virus. Thus PDGF-B gene is also called c-sis proto-oncogene. This report provides 3 TFOs (triplex-forming oligonucleotides) to inhibit the expression of c-sis/PDGF-B gene. The results from gel mobility shift analysis,in vitro transcription, DNase I footprinting and protein binding assays demonstrate that the TFOs we designed can form sequence-specific stable triplex with the target, and can effectively suppress the downstream gene transcription and inhibit transcription factors binding. They can be used for preparation of drugs to inhibit tumor growth and for the therapy of atherosclerosis, inflammation, etc.

PDGF B mRNA variants in human tumors with similarity to the v-sis oncogene: Expression of cellular PDGF B protein is associated with exon 1 divergence, but not with a 3'UTR splice variant

While platelet-derived growth factor, PDGF, is not regularly expressed in mesenchymal tissues, PDGF B mRNA is often found in tumors derived from these tissues. PDGF B protein is also present, but the protein levels in individual tumors do not appear to correlate well with those of the mRNA. PDGF B is homologous to the v-sis oncogene of simian sarcoma virus (SSV), and certain deletions confined to 3` and 5` non-coding sequences of PDGF B mRNA are consistently found in tumors induced by SSV and by a PDGF B retrovirus. Part of exon 1, including a non-coding GC-rich regulatory domain and the signal sequence as well as a 149 nucleotide long AU-rich stretch in the 3` non-coding region, are often lost. We hoped that this information could provide a clue to defective regulatory mechanisms present in human tumors and have searched for such mRNA variants in human sarcoma cell lines and soft tissue tumors. We identified a splice variant of PDGF B mRNA that, similar to v-sis, lacks the 149 nucleotide stretch and introduces an anomalous splice point between exons 6 and 7. This weakly abundant mRNA variant was co-expressed with the regular PDGF B mRNA, but its presence failed to show any association with increased levels of immunohistochemically detectable PDGF B protein. Instead, the highest levels of cellular PDGF B protein were found in samples with mRNAs showing exon 1 divergence. The changes in the 5` end of the mRNA were not accompanied by any genomic aberrations. Int. J. Cancer 85:211–222, 2000. ©2000 Wiley-Liss, Inc.

PDGF B mRNA variants in human tumors with similarity to the v-sis oncogene: Expression of cellular PDGF B protein is associated with exon 1 divergence, but not with a 3'UTR splice variant

While platelet-derived growth factor, PDGF, is not regularly expressed in mesenchymal tissues, PDGF B mRNA is often found in tumors derived from these tissues. PDGF B protein is also present, but the protein levels in individual tumors do not appear to correlate well with those of the mRNA. PDGF B is homologous to the v-sis oncogene of simian sarcoma virus (SSV), and certain deletions confined to 3; and 5; non-coding sequences of PDGF B mRNA are consistently found in tumors induced by SSV and by a PDGF B retrovirus. Part of exon 1, including a non-coding GC-rich regulatory domain and the signal sequence as well as a 149 nucleotide long AU-rich stretch in the 3; non-coding region, are often lost. We hoped that this information could provide a clue to defective regulatory mechanisms present in human tumors and have searched for such mRNA variants in human sarcoma cell lines and soft tissue tumors. We identified a splice variant of PDGF B mRNA that, similar to v-sis, lacks the 149 nucleotide stretch and introduces an anomalous splice point between exons 6 and 7. This weakly abundant mRNA variant was co-expressed with the regular PDGF B mRNA, but its presence failed to show any association with increased levels of immunohistochemically detectable PDGF B protein. Instead, the highest levels of cellular PDGF B protein were found in samples with mRNAs showing exon 1 divergence. The changes in the 5; end of the mRNA were not accompanied by any genomic aberrations.

Screening by tRNA primer extension analysis of porcine kidney mRNA libraries defines a novel endogenous porcine retroviral long terminal repeat.

We have taken advantage of the common requirement of all eukaryotic retroelements for a specific tRNA primer to initiate DNA synthesis and applied a previously described in vitro screening methodology to the analysis of in vivo porcine tissues for transcriptionally active retroviral sequences. A series of 18-base pair (bp) 3' tRNA oligomers complementary to established primer binding sites for a variety of vertebrate retroviruses, retrotransposons, and retroposons were applied to primer extension analysis of kidney poly(A) mRNA. Primer extension products are predicted to represent "strong stop" signals characteristic of the initial stages of retroviral transcription. Several extension products were cloned, sequenced, and analyzed as probes for screening the porcine genome for potentially active retroviral sequences. We used this strategy to identify and clone a 655-bp 5' long terminal repeat of a porcine retrovirus with significant homology to the simian sarcoma virus. This transcriptionally active virus has an 82-bp U5 region, a conserved AATAAA polyadenylation sequence, a 39-bp repeat reminiscent of other retroviral enhancers, and a unique glycine primer binding site. Our results suggest that tRNA primer cloning can effectively identify novel retroviral elements.

Development and validation of a Western immunoblot assay for detection of antibodies to porcine endogenous retrovirus.

Reports that pig endogenous retrovirus (PERV) infects human cells in vitro have heightened the importance of molecular and serologic monitoring of xenograft recipients for evidence of infection with PERV. We report the development and validation of a PERV-specific Western immunoblot assay for the diagnostic testing of porcine xenografts recipients. This assay is based upon the serological cross-reactivity observed between PERV variants capable of infecting human cells in vitro and other mammalian C type retroviruses. Strong reactivity between PERV expressing embryonic pig kidney PK-15 cells and antisera raised against whole virus preparations of murine leukemia virus, gibbon ape leukemia virus (GALV), and simian sarcoma-associated virus was demonstrated by an immunofluorescence assay, suggesting specific antigenic cross-reactivity between this group of viruses and PERV. Western immunoblot analysis demonstrated that anti-GALV antisera reacted with three proteins in PK-15 cells having molecular masses of 30, 55, and 66 kDa. Antisera specific for the Gag proteins of either GALV or simian sarcoma-associated virus reacted with the 30-kDa (major) and 55-kDa (minor) proteins present in PK-15 cells and in PERV-infected 293 human kidney cells, likely representing reactivity to the processed and precursor forms of the PERV Gag protein, respectively. No reactivity was seen in uninfected 293 cells. Analysis of plasma samples from 200 United States blood donors and from 58 human immunodeficiency virus-1, 18 human immunodeficiency virus-2, 13 human T-cell lymphotrophic virus-I, 21 human T-cell lymphotrophic virus-II, and 15 cytomegalovirus infected controls were negative. As this assay is based on PERV antigen derived from infected human cells, it clearly has the capacity to detect a serologic response towards PERV variants that have zoonotic potential and will allow for the accurate determination of PERV-specific seroreactivity in porcine xenograft recipients.

HTLV-I Protease, Reverse Transcriptase, and Integrase: The viral enzymes of replication.

O-32 Little is known about the three viral enzymes that are essential for HTLV-I replication-an aspartic acid protease (Pro), a reverse transcriptase (RT), and an integrase. We have cloned, expressed, and begun to characterize HTLV-I Pro, and HTLV-I proteins exhibiting reverse transcriptase and integrase activity. HTLV-I Pro cleaves peptides representing the HTLV-I retroviral processing sites P19/24 (APQVLPVMHPHG) and P24/15 (KTKVLVVQPK) with Km values of 470 μM and 310 μM and kcat values of 0.184 sec−1 and 0.0060 sec−1. Inhibition of HTLV-I Pro by a series of pepsin inhibitors (CS-I-22, 25, 27, 51, and 52) yielded Ki values for inhibition of HTLV-I Pro that ranged from 7 nM to 10 μM, while the Ki values for inhibition of pepsin by the pepsin inhibitors ranged from 0.72 to 19.2 nM. More importantly, inhibition of HTLV-I Pro by a series of HIV protease inhibitors (JG-365, MES13-099, N1270, N1395, N1460, and N-1465) yielded Ki values that ranged from 6 nM to 127 μM, while the Ki values for inhibition of HIV-1 Pro by the HIV Pro inhibitors ranged from 0.24 nM to 1.0 μM. This suggests that currently employed HIV-1 Pro inhibitors would not be effective for the treatment of HTLV-I infections. Alignment of known RT's to the sequence of HTLV-I MT2 Pol protein indicates that HTLV-I RT extends from Pro33 to Val598. The protein was expressed, was shown to exhibit RT activity, and was found to cross react with antibodies to the RT's of Gibbon Ape Leukemia Virus and Simian Sarcoma Virus. These antibodies were also found to react with a low abundance protein from HTLV-I virions.

Mechanism of action and in vivo role of platelet-derived growth factor.

Platelet-derived growth factor (PDGF) is a major mitogen for connective tissue cells and certain other cell types. It is a dimeric molecule consisting of disulfide-bonded, structurally similar A- and B-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors, denoted the alpha-receptor and the beta-receptor. Activation of PDGF receptors leads to stimulation of cell growth, but also to changes in cell shape and motility; PDGF induces reorganization of the actin filament system and stimulates chemotaxis, i.e., a directed cell movement toward a gradient of PDGF. In vivo, PDGF has important roles during the embryonic development as well as during wound healing. Moreover, overactivity of PDGF has been implicated in several pathological conditions. The sis oncogene of simian sarcoma virus (SSV) is related to the B-chain of PDGF, and SSV transformation involves autocrine stimulation by a PDGF-like molecule. Similarly, overproduction of PDGF may be involved in autocrine and paracrine growth stimulation of human tumors. Overactivity of PDGF has, in addition, been implicated in nonmalignant conditions characterized by an increased cell proliferation, such as atherosclerosis and fibrotic conditions. This review discusses structural and functional properties of PDGF and PDGF receptors, the mechanism whereby PDGF exerts its cellular effects, and the role of PDGF in normal and diseased tissues.

Simian Sarcoma-Associated Virus Fails To Infect Chinese Hamster Cells despite the Presence of Functional Gibbon Ape Leukemia Virus Receptors

We have sequenced the envelope genes from each of the five members of the gibbon ape leukemia virus (GALV) family of type C retroviruses. Four of the GALVs, including GALV strain SEATO (GALV-S), were originally isolated from gibbon apes, whereas the fifth member of this family, simian sarcoma-associated virus (SSAV), was isolated from a woolly monkey and shares 78% amino acid identity with GALV-S. To determine whether these viruses have identical host ranges, we evaluated the susceptibility of several cell lines to either GALV-S or SSAV infection. GALV-S and SSAV have the same host range with the exception of Chinese hamster lung E36 cells, which are susceptible to GALV-S but not SSAV. We used retroviral vectors that differ only in their envelope composition (e.g., they contain either SSAV or GALV-S envelope protein) to show that the envelope of SSAV restricts entry into E36 cells. Although unable to infect E36 cells, SSAV infects GALV-resistant murine cells expressing the E36-derived viral receptor, HaPit2. These results suggest that the receptors present on E36 cells function for SSAV. We have constructed several vectors containing GALV-S/SSAV chimeric envelope proteins to map the region of the SSAV envelope that blocks infection of E36 cells. Vectors bearing chimeric envelopes comprised of the N-terminal region of the GALV-S SU protein and the C-terminal region of SSAV infect E36 cells, whereas vectors containing the N-terminal portion of the SSAV SU protein and C-terminal portion of GALV-S fail to infect E36 cells. This finding indicates that the region of the SSAV envelope protein responsible for restricting SSAV infection of E36 cells lies within its amino-terminal region.

Going for the GAP.

Going for the GAP.

Characterization of a C-type retrovirus isolated from an HIV infected cell line: complete nucleotide sequence.

As previously reported, a C-type retrovirus, referred to as retrovirus X was isolated from HIV infected cells. In order to further characterize this virus, the proviral DNA was cloned and sequenced. The organization of the genome (8379 bp) appeared to be typical of the mammalian type C retroviruses. The virus was shown to be closely related to the gibbon ape leukaemia virus (GALV) with 87% similarity when the sequence was compared with the published genome of the Seato strain of GALV. At the level of the long terminal repeat where comparison was possible with other strains, the closest relationship was found with the San Francisco strain of GALV and with the simian sarcoma virus. These results suggest that the isolate should be considered as a strain of GALV.

Expression of v-src in mammary epithelial cells induces transcription via STAT3

Transgenic mouse models of mammary tumorigenesis and analyses of human breast tumour samples have indicated a role for Src proteins in the tumorigenic process. The downstream effectors of Src function in mammary epithelial cells are less well understood. STAT proteins constitute a family of transcription factors whose activation by cytokine and non-cytokine receptors leads to tyrosine phosphorylation, dimerization and translocation from the cytoplasm to the nucleus. In the nucleus they activate the transcription of specific genes by binding to consensus DNA elements. STATs 1 and 3 can be activated by both cytokine and non-cytokine receptors, and bind as homodimers or heterodimers to viral simian sarcoma virus (sis)-inducible elements such as that found in the c-fos promoter. Here we report that one of the downstream effectors of Src function in mammary epithelial cells is STAT3. We demonstrate that v-src expression in mammary epithelial cells induces Tyr-705 phosphorylation, nuclear translocation and DNA binding of STAT3. Furthermore, we demonstrate that v-src can induce STAT3-dependent transcription. These observations are the first direct evidence that v-src can regulate transcription through the activation of STAT proteins, and add a further level of complexity to the understanding of the mode of action of v-src.

Platelet-derived growth factor-B induces transformation of fibrocytes into spindle-shaped myofibroblasts in vivo.

Platelet-derived growth factor (PDGF) has a targeted activity on mesenchymal cells, but the in vivo effects of PDGF are not well understood. We have applied about 3 microg of PDGF-A and PDGF-B on the differentiated chorioallantoic membrane (CAM) of 13-day-old chick embryos. After 1-3 days, specimens were evaluated macroscopically, histologically with semi- and ultrathin sections, and immunohistologically with antibodies against smooth muscle alpha-actin (alphaSMA), desmin, and fibronectin (FN). Proliferation studies were performed according to the 5-bromo-2-deoxyuridine (BrdU)/anti-BrdU method. We did not observe effects of PDGF-A. PDGF-B induced proliferation of fibrocytes and their transformation into myofibroblasts. Bundles of spindle-shaped myofibroblasts accumulated beneath the chorionic epithelium. These cells were strongly positive for alphaSMA and FN, but negative for desmin. They possessed a well developed rough endoplasmic reticulum and bundles of microfilaments anchoring in the cell membrane. Our results suggest that PDGF-B is a "transforming" growth factor with important functions during formation of granulation tissue which are closely comparable to the effects of the PDGF-B-like protein of simian sarcoma virus. PDGF-B also induced vascular alterations in the CAM, which, however, appeared to be a secondary effect. While the intra-chorionic capillaries were lost, an accumulation of small vessels positive for alphaSMA was observed. This indicates a function for PDGF-B during segregation of main vessels from a primary vascular plexus.