Early and transient reverse transcription during primary deltaretroviral infection of sheep

Pomier, Carole; Alcaraz, Maria Teresa Sanchez; Debacq, Christophe; Lançon, Agnès; Kerkhofs, Pierre; Willems, Luc; Wattel, Éric; Mortreux, Franck

doi:10.1186/1742-4690-5-16

Cited by 18 publications

(27 citation statements)

References 36 publications

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“…At first glance, it seems obvious that the proviral loads would be increased if infection of new target cells by mutant N230E is enhanced. However, cell-to-cell transmission can only be significantly detected at the very early stages of infection because of a very active immune response that only tolerates clonal expansion (54,55). Consistently, a TM mutant impaired in cell fusion (A60V) (56) can replicate at wild-type levels and induce lymphoma/leukemia in sheep, emphasizing the primordial role of clonal replication during chronic infection.…”

Section: Discussionmentioning

confidence: 80%

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: Discussionmentioning

confidence: 80%

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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“…In particular, early infection appears to be critical at determining the different populations of cells (i.e. clones) that will subsequently thrive and expand during pathogenesis [10], [11], [17]. The mechanisms undergoing during this initial period of HTLV-1 infection cannot be addressed because of lack of samples (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…a population of cells carrying the provirus at a given site of the host genome). Animal models using experimental inoculation of squirrel monkey with HTLV-1 or sheep with BLV demonstrated that the infectious cycle dominates early infection and finishes 1 to 8 months later [10], [11]. Thereafter, the proviral load (PVL) is mainly maintained by mitotic replication of infected cells [12]–[15].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2013

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Deltaretroviruses such as human T-lymphotropic virus type 1 (HTLV-1) and bovine leukemia virus (BLV) induce a persistent infection that remains generally asymptomatic but can also lead to leukemia or lymphoma. These viruses replicate by infecting new lymphocytes (i.e. the infectious cycle) or via clonal expansion of the infected cells (mitotic cycle). The relative importance of these two cycles in viral replication varies during infection. The majority of infected clones are created early before the onset of an efficient immune response. Later on, the main replication route is mitotic expansion of pre-existing infected clones. Due to the paucity of available samples and for ethical reasons, only scarce data is available on early infection by HTLV-1. Therefore, we addressed this question in a comparative BLV model. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the BLV-infected cells population (i.e. the number of distinct clones and abundance of each clone). We found that BLV propagation shifts from cell neoinfection to clonal proliferation in about 2 months from inoculation. Initially, BLV proviral integration significantly favors transcribed regions of the genome. Negative selection then eliminates 97% of the clones detected at seroconversion and disfavors BLV-infected cells carrying a provirus located close to a promoter or a gene. Nevertheless, among the surviving proviruses, clone abundance positively correlates with proximity of the provirus to a transcribed region. Two opposite forces thus operate during primary infection and dictate the fate of long term clonal composition: (1) initial integration inside genes or promoters and (2) host negative selection disfavoring proviruses located next to transcribed regions. The result of this initial response will contribute to the proviral load set point value as clonal abundance will benefit from carrying a provirus in transcribed regions.

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“…This conclusion is consistent with previous evidence from studies of adult seroconverters 38 and animal models. 39,40 By comparing the genomic features associated with UISs identified in vitro with those of the UISs isolated in vivo (and particularly those of low abundance that make up the majority of all UISs), regardless of disease status, we show that proviruses inserted in silenced DNA were more likely to establish long-lived infected T-cell clones (Figure 4). We hypothesize that lower proviral expression associated with transcriptional silencing of surrounding host DNA allows the infected cell to escape elimination by the immune response.…”

Section: Discussionmentioning

confidence: 99%

The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clones

Gillet

Malani

Melamed

et al. 2011

Blood

271

467

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Human T-lymphotropic virus type 1 (HTLV-1) persists by driving clonal proliferation of infected T lymphocytes. A high proviral load predisposes to HTLV-1-associated diseases. Yet the reasons for the variation within and between persons in the abundance of HTLV-1-infected clones remain unknown. We devised a highthroughput protocol to map the genomic location and quantify the abundance of > 91 000 unique insertion sites of the provirus from 61 HTLV-1 ؉ persons and > 2100 sites from in vitro infection. We show that a typical HTLV-1-infected host carries between 500 and 5000 unique insertion sites. We demonstrate that negative selection dominates during chronic infection, favoring establishment of proviruses integrated in transcriptionally silenced DNA: this selection is significantly stronger in asymptomatic carriers. We define a parameter, the oligoclonality index, to quantify clonality. The high proviral load characteristic of HTLV-1- IntroductionHuman T-lymphotropic virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATLL), HTLV-1-associated myelopathy/ tropical spastic paraparesis (HAM/TSP), uveitis, and infective dermatitis. It is estimated that 15 to 20 million persons live with HTLV-1 infection worldwide. A small proportion (up to 7%, depending on the area) of HTLV-1-infected persons develop disease, whereas the majority remain asymptomatic carriers (ACs). Infection occurs via breastfeeding, transfusion of infected cellular blood products, or sexual intercourse. Symptoms appear after a long period (years or decades) of clinical latency. 1 The HTLV-1 proviral load (PVL) remains stable within each infected person and correlates with the outcome of infection. However, the PVL varies widely among infected people, even within a particular diagnostic group. [2][3][4] The sequence of HTLV-1 is also stable within a person, 5,6 indicating that the PVL is maintained in vivo mainly by mitosis of infected cells during the chronic phase of the infection. This interpretation is supported by the observation that individual clones of infected cells can persist in patients for several years. 7-9 Thus, it has been hypothesized that infectious transmission of HTLV-1 is important early in infection across the virologic synapse, 10 whereas mitotic replication is responsible for maintaining proviral load once a persistent infection has been established and reached an equilibrium with the immune response. 11 In approximately 5% of infected people, persistent clonal proliferation culminates in malignant transformation in the disease ATLL. 7,8 The leukemic clones carry generally one (complete or defective) provirus per cell. [12][13][14] There has been a longstanding debate on the question of whether HTLV-1 is latent or persistently expressed in vivo. Persistent expression is strongly suggested by the extensive evidence that the strong, chronically activated cytotoxic T lymphocyte (CTL) response to HTLV-1 limits the proviral load and reduces the risk of HAM/TSP. 11 Furthermore, there is both experimental evidence 15 and th...

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Early and transient reverse transcription during primary deltaretroviral infection of sheep

Cited by 18 publications

References 36 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

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

The host genomic environment of the provirus determines the abundance of HTLV-1–infected T-cell clones

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