Ablation of non-coding RNAs affects bovine leukemia virus B lymphocyte proliferation and abrogates oncogenesis

Safari, Roghaiyeh; Jacques, Jean-Rock; Brostaux, Yves; Willems, Luc

doi:10.1371/journal.ppat.1008502

Cited by 20 publications

(18 citation statements)

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“…Additionally, the seed of one BLV miRNA (BLV-miR-B4) is similar to that of host miR-29 associated with B-cell neoplasms [ 22 , 23 ]. Consistent with the notion that BLV-miR-B4 contributes to BLV-associated tumorigenesis, the main pathway driven by BLV miRNAs pertains to proliferation of B lymphocytes [ 9 ]. Moreover, the miRNAs interfere with host immunity and are associated with reduced expression of genes involved in B-cell differentiation [ 24 ].…”

Section: Introductionsupporting

confidence: 66%

“…The propagation of BLV in BLV-infected cattle depends mainly on the mitotic division of infected cells (clonal expansion) [ 7 ]; it is also thought that a small population of the BLV-infected cells produce infectious virions [ 8 ]. The level of viral propagation in BLV-infected cattle can be assessed by the proviral load (PVL), defined as the number of proviral copies in blood cells [ 9 ]. The PVL in PL is significantly higher than in asymptomatic BLV-infected cattle [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Based on the widely described properties of the BLV-encoded Tax protein [ 17 , 18 ], it is assumed that this protein triggers cell proliferation. Additionally, the selective growth advantage of the infected cells is spurred by viral non-coding RNAs (i.e., lncRNAs and miRNAs) [ 9 , 19 , 20 , 21 ]. The BLV provirus constitutively expresses antisense transcripts AS1-S/L and AS2 in all leukemic and asymptomatic individuals, which may play a role in the regulation of BLV [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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Analysis of Nucleotide Sequence of Tax, miRNA and LTR of Bovine Leukemia Virus in Cattle with Different Levels of Persistent Lymphocytosis in Russia

et al. 2021

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Bovine Leukemia Virus (BLV) is the etiological agent of enzootic bovine leucosis (EBL), a lymphoproliferative disease of the bovine species. In BLV-infected cells, the long terminal repeat (LTR), the viral Tax protein and viral miRNAs promote viral and cell proliferation as well as tumorigenesis. Although their respective roles are decisive in BLV biology, little is known about the genetic sequence variation of these parts of the BLV genome and their impact on disease outcome. Therefore, the objective of this study was to assess the relationship between disease progression and sequence variation of the BLV Tax, miRNA and LTR regions in infected animals displaying either low or high levels of persistent lymphocytosis (PL). A statistically significant association was observed between the A(+187)C polymorphism in the downstream activator sequence (DAS) region in LTR (p-value = 0.00737) and high lymphocytosis. Our study also showed that the mutation (−4)G in the CAP site occurred in 70% of isolates with low PL and was not found in the high PL group. Conversely, the mutations G(−133)A/C in CRE2 (46.7%), C(+160)T in DAS (30%) and A(310)del in BLV-mir-B4-5p, A(357)G in BLV-mir-B4-3p, A(462)G in BLV-mir-B5-5p, and GA(497–498)AG in BLV-mir-B5-3p (26.5%) were often seen in isolates with high PL and did not occur in the low PL group. In conclusion, we found several significant polymorphisms among BLV genomic sequences in Russia that would explain a progression towards higher or lower lymphoproliferation. The data presented in this article enabled the classification between two different genotypes; however, clear association between genotypes and the PL development was not found.

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Section: Introductionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Analysis of Nucleotide Sequence of Tax, miRNA and LTR of Bovine Leukemia Virus in Cattle with Different Levels of Persistent Lymphocytosis in Russia

et al. 2021

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“…Two protein coding genes, Tax and Rex, are considered CIS-transcriptional activators that bind to the 3’ LTR and are commonly implicated in viral oncogenesis [ 76 , 77 ]. Unlike other retroviruses, BLV also encodes 10 microRNAs and other long non-coding RNAs, in which their expression levels are now being shown to associate with BLV pathogenesis [ 78 , 79 ]. Though the genomic architecture is not unique to other retroviruses, such as HTLV-1 and HIV, many knowledge gaps still remain as to how genetic variation within accessory genes may confer differences in transmissibility, virulence and pathogenicity.…”

Section: The Blv Viral Genomementioning

confidence: 99%

Current Developments in the Epidemiology and Control of Enzootic Bovine Leukosis as Caused by Bovine Leukemia Virus

Bartlett

Ruggiero

Hutchinson³

et al. 2020

Pathogens

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Enzootic Bovine Leukosis (EBL) caused by the bovine leukemia virus (BLV) has been eradicated in over 20 countries. In contrast, the U.S. and many other nations are experiencing increasing prevalence in the absence of efforts to control transmission. Recent studies have shown that BLV infection in dairy cattle has a greater impact beyond the long-recognized lymphoma development that occurs in <5% of infected cattle. Like other retroviruses, BLV appears to cause multiple immune system disruptions, affecting both cellular and humoral immunity, which are likely responsible for increasingly documented associations with decreased dairy production and decreased productive lifespan. Realization of these economic losses has increased interest in controlling BLV using technology that was unavailable decades ago, when many nations eradicated BLV via traditional antibody testing and slaughter methods. This traditional control is not economically feasible for many nations where the average herd antibody prevalence is rapidly approaching 50%. The ELISA screening of cattle with follow-up testing via qPCR for proviral load helps prioritize the most infectious cattle for segregation or culling. The efficacy of this approach has been demonstrated in at least four herds. Breeding cattle for resistance to BLV disease progression also appears to hold promise, and several laboratories are working on BLV vaccines. There are many research priorities for a wide variety of disciplines, especially including the need to investigate the reports linking BLV and human breast cancer.

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“…Ablation of BLV miRNAs impacts fitness and suppression of oncogenicity in the natural host [ 245 ]. The main mode of action the BLV miRNAs occurs through increased proliferation of B lymphocytes [ 246 ]. In contrast to BLV and HIV, no virally-encoded miRNA could be identified in HTLV-1.…”

Section: Role Of Non-coding Rnas In Regulation Of Deltaretrovirus mentioning

confidence: 99%

Regulation of Expression and Latency in BLV and HTLV

Pluta

Jaworski

Douville

2020

Viruses

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Human T-lymphotrophic virus type 1 (HTLV-1) and Bovine leukemia virus (BLV) belong to the Deltaretrovirus genus. HTLV-1 is the etiologic agent of the highly aggressive and currently incurable cancer adult T-cell leukemia (ATL) and a neurological disease HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). BLV causes neoplastic proliferation of B cells in cattle: enzootic bovine leucosis (EBL). Despite the severity of these conditions, infection by HTLV-1 and BLV appear in most cases clinically asymptomatic. These viruses can undergo latency in their hosts. The silencing of proviral gene expression and maintenance of latency are central for the establishment of persistent infection, as well as for pathogenesis in vivo. In this review, we will present the mechanisms that control proviral activation and retroviral latency in deltaretroviruses, in comparison with other exogenous retroviruses. The 5′ long terminal repeats (5′-LTRs) play a main role in controlling viral gene expression. While the regulation of transcription initiation is a major mechanism of silencing, we discuss topics that include (i) the epigenetic control of the provirus, (ii) the cis-elements present in the LTR, (iii) enhancers with cell-type specific regulatory functions, (iv) the role of virally-encoded transactivator proteins, (v) the role of repressors in transcription and silencing, (vi) the effect of hormonal signaling, (vii) implications of LTR variability on transcription and latency, and (viii) the regulatory role of non-coding RNAs. Finally, we discuss how a better understanding of these mechanisms may allow for the development of more effective treatments against Deltaretroviruses.

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Ablation of non-coding RNAs affects bovine leukemia virus B lymphocyte proliferation and abrogates oncogenesis

Cited by 20 publications

References 61 publications

Analysis of Nucleotide Sequence of Tax, miRNA and LTR of Bovine Leukemia Virus in Cattle with Different Levels of Persistent Lymphocytosis in Russia

Analysis of Nucleotide Sequence of Tax, miRNA and LTR of Bovine Leukemia Virus in Cattle with Different Levels of Persistent Lymphocytosis in Russia

Current Developments in the Epidemiology and Control of Enzootic Bovine Leukosis as Caused by Bovine Leukemia Virus

Regulation of Expression and Latency in BLV and HTLV

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