Massive Depletion of Bovine Leukemia Virus Proviral Clones Located in Genomic Transcriptionally Active Sites during Primary Infection

Gillet, Nicolas; Gutiérrez, Gerónimo; Rodríguez, Sabrina; Brogniez, Alix de; Renotte, Nathelie; Álvarez, Irene; Trono, K.; Willems, Luc

doi:10.1371/journal.ppat.1003687

Cited by 84 publications

(92 citation statements)

References 65 publications

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“…Animals were maintained in L2-restricted containment in agreement with national and European regulations under registration number LA1900600. Sheep were inoculated with BLV proviruses cloned into a bacterial vector, as previously described (23,24).…”

Section: Methodsmentioning

confidence: 99%

Mutation of a Single Envelope N-Linked Glycosylation Site Enhances the Pathogenicity of Bovine Leukemia Virus

Brogniez

Bouzar

Jacques

et al. 2015

J Virol

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Viruses have coevolved with their host to ensure efficient replication and transmission without inducing excessive pathogenicity that would indirectly impair their persistence. This is exemplified by the bovine leukemia virus (BLV) system in which lymphoproliferative disorders develop in ruminants after latency periods of several years. In principle, the equilibrium reached between the virus and its host could be disrupted by emergence of more pathogenic strains. Intriguingly but fortunately, such a hyperpathogenic BLV strain was never observed in the field or designed in vitro. In this study, we sought to understand the role of envelope N-linked glycosylation with the hypothesis that this posttranslational modification could either favor BLV infection by allowing viral entry or allow immune escape by using glycans as a shield. Using reverse genetics of an infectious molecular provirus, we identified a N-linked envelope glycosylation site (N230) that limits viral replication and pathogenicity. Indeed, mutation N230E unexpectedly leads to enhanced fusogenicity and protein stability. There is no satisfactory treatment for HAM/TSP, and the prognosis for ATLL is still poor despite improved therapies (2). BLV is responsible for major economic losses in cattle due to export limitations, carcass condemnations, and reduction in milk production. BLV infection also correlates with a significant morbidity resulting from opportunistic infections and a decrease in longevity due to tumor development (3). In a proportion (i.e., about one third) of infected cattle, BLV induces a lymphoproliferative disease called persistent lymphocytosis. After a latency period of several years, BLV infection also leads to leukemia and/or lymphoma in a minority (5%) of the infected animals. However, the majority of BLV carriers remain clinically healthy and acts as asymptomatic carriers for viral spread (4). Besides its natural hosts (i.e., cattle, zebu, and water buffalo), BLV can be experimentally transmitted to sheep and goats, where leukemia/lymphoma develops after shorter latency periods (5-7).Retroviral envelope glycoproteins play an important role in the viral life cycle: they contain the recognition site required for entry and mediate cell fusion (8). The BLV envelope is composed of two glycoproteins: a surface (SU) protein, Gp51, and a transmembrane (TM) protein, Gp30, derived from the proteolytic cleavage of a common precursor (gpr72) encoded by the env gene (9-11). The SU protein is N-glycosylated in the rough endoplasmic reticulum by covalent attachment of oligosaccharide chains (12). Although the role of BLV SU-linked glycans is currently unknown, it is expected that N-glycosylation is required for protein folding, stability, or solubility (13). Furthermore, N-glycans are also likely involved in transport of BLV envelope proteins to the cell membrane, binding to cellular receptors and cell-to-cell fusion (14-18) similarly to glycans of the human immunodeficiency virus (HIV) envelope glycoprotein that modulate fusogenicity ...

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Section: Methodsmentioning

confidence: 99%

Mutation of a Single Envelope N-Linked Glycosylation Site Enhances the Pathogenicity of Bovine Leukemia Virus

Brogniez

Bouzar

Jacques

et al. 2015

J Virol

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“…-genes promoting viral replication and persistence (Tax and HBZ) (Matsuoka and Jeang, 2007); -modes of viral entry and replication (infectious and mitotic cycles) (Ghez et al, 2010;Boxus et al, 2012;Gillet et al, 2011Gillet et al, , 2013Sibon et al, 2006); -genomic and epigenetic mechanisms leading to ATL (oncogenic stress, driver mutations) (Kataoka et al, 2015;Yamagishi et al, 2012); -the role of the immune response in the control of infection (Asquith and Bangham, 2008); -the pathogenic potential of HTLV-2, -3 and -4 (Calattini et al, 2006).…”

Section: Perform Basic Research To Unravel Mechanisms Of Viral Persismentioning

confidence: 99%

Reducing the global burden of HTLV-1 infection: An agenda for research and action

et al. 2017

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a b s t r a c tEven though an estimated 10e20 million people worldwide are infected with the oncogenic retrovirus, human T-lymphotropic virus type 1 (HTLV-1), its epidemiology is poorly understood, and little effort has been made to reduce its prevalence. In response to this situation, the Global Virus Network launched a taskforce in 2014 to develop new methods of prevention and treatment of HTLV-1 infection and promote basic research. HTLV-1 is the etiological agent of two life-threatening diseases, adult T-cell leukemia and HTLV-associated myelopathy/tropical spastic paraparesis, for which no effective therapy is currently available. Although the modes of transmission of HTLV-1 resemble those of the more familiar HIV-1, routine diagnostic methods are generally unavailable to support the prevention of new infections. In * Corresponding author. Molecular and Cellular Epigenetics, Interdisciplinary Cluster for Applied Genoproteomics (GIGA) of University of Liege (ULg), B34, 1 Avenue de l'Hôpital, 4000, Sart-Tilman, Liege, Belgium.E-mail address: luc.willems@ulg.ac.be (L. Willems). Contents lists available at ScienceDirect Antiviral Researchj o u rn a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / a n t iv i r a l the present article, the Taskforce proposes a series of actions to expand epidemiological studies; increase research on mechanisms of HTLV-1 persistence, replication and pathogenesis; discover effective treatments; and develop prophylactic and therapeutic vaccines.

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“…The infection then spreads through clonal expansion of infected host cells, without evidence for reverse transcription. [17][18][19] Specific antibodies are mainly directed toward the structural envelope gp51 and capsid p24 proteins. These antiviral activities persist throughout the animal's life, indicating that the immune system is permanently stimulated by BLV antigens.…”

Section: Biological Properties Of Blv and Initial Events Following Blmentioning

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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Massive Depletion of Bovine Leukemia Virus Proviral Clones Located in Genomic Transcriptionally Active Sites during Primary Infection

Cited by 84 publications

References 65 publications

Mutation of a Single Envelope N-Linked Glycosylation Site Enhances the Pathogenicity of Bovine Leukemia Virus

Mutation of a Single Envelope N-Linked Glycosylation Site Enhances the Pathogenicity of Bovine Leukemia Virus

Reducing the global burden of HTLV-1 infection: An agenda for research and action

Bovine leukemia virus: current perspectives

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