Cis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis

Rosewick, Nicolas; Durkin, Keith; Artesi, Maria; Marçais, Ambroise; Hahaut, Vincent; Griebel, Philip; Arsic, Natasa; Avettand-Fènoël, Véronique; Burny, Arsène; Charlier, Carole; Hermine, Olivier; Georges, Michel; Broeke, Anne Van den

doi:10.1038/ncomms15264

Cited by 82 publications

(135 citation statements)

References 68 publications

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“…To discriminate between these two hypotheses, we used an improved high-throughput sequencing (HTS) method to simultaneously map proviral integration sites and measure the abundance of the corresponding clones40.…”

Section: Resultsmentioning

confidence: 99%

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HTLV-1-induced leukotriene B4 secretion by T cells promotes T cell recruitment and virus propagation

et al. 2017

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The human T-lymphotropic virus type 1 (HTLV-1) is efficiently transmitted through cellular contacts. While the molecular mechanisms of viral cell-to-cell propagation have been extensively studied in vitro, those facilitating the encounter between infected and target cells remain unknown. In this study, we demonstrate that HTLV-1-infected CD4 T cells secrete a potent chemoattractant, leukotriene B4 (LTB4). LTB4 secretion is dependent on Tax-induced transactivation of the pla2g4c gene, which encodes the cytosolic phospholipase A2 gamma. Inhibition of LTB4 secretion or LTB4 receptor knockdown on target cells reduces T-cell recruitment, cellular contact formation and virus propagation in vitro. Finally, blocking the synthesis of LTB4 in a humanized mouse model of HTLV-1 infection significantly reduces proviral load. This results from a decrease in the number of infected clones while their expansion is not impaired. This study shows the critical role of LTB4 secretion in HTLV-1 transmission both in vitro and in vivo.

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Section: Resultsmentioning

confidence: 99%

“…Given the low PVLs observed in MK886-treated animals, we applied an improved HTS method, which includes several critical modifications in library preparation, and increases the sensitivity of the assay40.…”

Section: Discussionmentioning

confidence: 99%

HTLV-1-induced leukotriene B4 secretion by T cells promotes T cell recruitment and virus propagation

et al. 2017

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“…115 However, no proof of concept has been shown, nor has preliminary data been published concerning the identity of the provirus mutated/deleted genes, the immune protection conferred to the vaccinated animals in the long term, the safety assessment of the vaccine, and the proposed strategy to be used to differentiate vaccinated from infected animals. The recent evidence on the role of viral miRNA in BLV pathogenesis 14 together with the finding that BLV proviruses are integrated near cancer drivers, whose expression is perturbed by the integrated proviruses, 16 further emphasizes the need of caution on retroviral live-attenuated vaccines. It should also be borne in mind that the use of an attenuated retroviral vaccine implies a risk for disruption of genes upon insertion into the cellular genome, preventing their expression, and there is also the risk of reversion to virulent, oncogenic forms in the long run.…”

Section: -101mentioning

confidence: 99%

Bovine leukemia virus: current perspectives

Juliarena¹,

Barrios²,

Lützelschwab³

et al. 2017

VAAT

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Enzootic bovine leukosis, caused by bovine leukemia virus (BLV), is the most common neoplasm of dairy cattle. Although beef and dairy cattle are susceptible to BLV infection and BLV-associated lymphosarcoma, the disease is more commonly detected in dairy herds, mostly because of the management practices in dairy farms. The pathogenicity of BLV in its natural host, the bovine, depends mainly on the resistance/susceptibility genetics of the animal. The majority of infected cattle are asymptomatic, promoting the extremely high dissemination rate of BLV in many bovine populations. The important productive losses caused by the BLV, added to the health risk of maintaining populations with a high prevalence of infection with a retrovirus, generates the need to implement control measures. Different strategies to control the virus have been attempted. The most effective approach is to identify and cull the totality of infected cattle in the herd. However, this approach is not suitable for herds with high prevalence of infection. At present, no treatment or vaccine has proven effective for the control of BLV. Thus far, the genetic selection of resistant animals emerges as a natural strategy for the containment of the BLV dissemination. In natural conditions, most of the infected, resistant cattle can control the infection, and therefore do not pass the virus to other animals, gradually decreasing the prevalence of the herd.

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“…Integration sites and PVL were determined as previously described in Rosewick et al 2017 4 and Artesi et al 2017 14 .…”

Section: Identification Of Proviral Integration Sites (Illumina) Andmentioning

confidence: 99%

“…Methods based on ligation mediated PCR and Illumina sequencing have facilitated the identification of hundreds of thousands of insertion sites in exogenous viruses such as Human T-cell leukemia virus-1 (HTLV-1) 2 and Human immunodeficiency virus (HIV-1) 3 . These techniques have shown that in HTLV-1 2 , Bovine Leukemia Virus (BLV) 4 , Avian Leukosis Virus (ALV) 5 and HIV-1 6 integration sites are not random, most likely reflecting clonal selection. In HIV-1 it has also become apparent that provirus integration can drive clonal expansion 3 and contribute to the HIV-1 reservoir, placing a major road block in the way of a complete cure.…”

Section: Introductionmentioning

confidence: 99%

Pooled CRISPR Inverse PCR sequencing (PCIP-seq): simultaneous sequencing of retroviral insertion points and the associated provirus in thousands of cells with long reads

Artesi

Hahaut

Cole

et al. 2019

Preprint

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Retroviral infections create a large population of cells, each defined by a unique proviral insertion site. Methods based on short-read high throughput sequencing can identify thousands of insertion sites, but the proviruses within remain unobserved. We have developed Pooled CRISPR Inverse PCR sequencing (PCIP-seq), a method that leverages long reads on the Oxford Nanopore MinION platform to sequence the insertion site and its associated provirus. We have applied the technique to three exogenous retroviruses, HTLV-1, HIV-1 and BLV, as well as endogenous retroviruses in both cattle and sheep. The long reads of PCIP-seq improved the accuracy of insertion site identification in repetitive regions of the genome. The high efficiency of the method facilitated the identification of tens of thousands of insertion sites in a single sample. We observed thousands of SNPs and dozens of structural variants within proviruses and uncovered evidence of viral hypermutation, recombination and recurrent selection.

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Cis-perturbation of cancer drivers by the HTLV-1/BLV proviruses is an early determinant of leukemogenesis

Cited by 82 publications

References 68 publications

HTLV-1-induced leukotriene B4 secretion by T cells promotes T cell recruitment and virus propagation

HTLV-1-induced leukotriene B4 secretion by T cells promotes T cell recruitment and virus propagation

Bovine leukemia virus: current perspectives

Pooled CRISPR Inverse PCR sequencing (PCIP-seq): simultaneous sequencing of retroviral insertion points and the associated provirus in thousands of cells with long reads

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