Neuropathogenic murine leukemia virus TR1.3 induces selective syncytia formation of brain capillary endothelium

Landers, Maeran Chung; Dugger, Natalie V.; Quadros, Marlene R.D.; Hoffman, Paul M.; Gaulton, Glen N.

doi:10.1016/j.virol.2003.12.002

Cited by 5 publications

(4 citation statements)

References 31 publications

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“…Collectively, these data suggest that the TR1.3 virus induces cell fusion primarily by the FFWO pathway. Previous work from our group showed that NIH 3T3 cells and primary BCEC undergo FFWO when exposed to high concentrations of TR1.3 or W102G virus but not FB29 virus, supporting the conclusions of the results presented here (10,28).…”

Section: Discussionsupporting

confidence: 91%

“…The onset of disease parallels the appearance of large multinucleated syncytia exclusively in brain capillary endothelial cells (BCEC) (37). Similarly, although primary endothelial cell cultures derived from the brain, kidney, liver, and lung are equivalently infected by TR1.3, cell fusion occurs only in BCEC (28). The aggressive fusion potential of TR1.3 is also evident in cell culture lines; unlike most MLVs, TR1.3 induces syncytium formation in SC-1 and NIH 3T3 murine fibroblast cells (10,39).…”

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confidence: 99%

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TR1.3 Viral Pathogenesis and Syncytium Formation Are Linked to Env-Gag Cooperation

Murphy

Gaulton

2007

J Virol

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Infection with murine leukemia virus (MLV) TR1.3 or the related molecular construct W102G causes severe neuropathology in vivo. Infection is causally linked to the development of extensive syncytia in brain capillary endothelial cells (BCEC). These viruses also induce cell fusion of murine cell lines, such as SC-1 and NIH 3T3, which are otherwise resistant to MLV-induced syncytium formation. Although the virulence of these viruses maps within the env gene, the mechanism of fusion enhancement is not fully determined. To this end, we examined the capacity of the syncytium-inducing (SI) TR1.3 and W102G MLVs to overcome the fusion inhibitory activity inherent in the full-length Env cytoplasmic tail. These studies showed that the TR1.3 and W102G Envs did not induce premature cleavage of p2E, nor did they override p2E fusion inhibition. Indeed, in the presence of mutations that disrupt p2E function, the TR1.3 and W102G Envs significantly increased the extent of cell fusion compared to that with the non-syncytium-inducing MLV FB29. Surprisingly, we also observed that TR1.3 and W102G Envs failed to elicit syncytium formation in these in vitro assays. Coexpression of gag-pol with env restored syncytium formation, and accordingly, mutations within gag-pol were used to examine the minimal functional requirements for the SI phenotype. The results indicate that both gag-dependent particle budding and cleavage of p2E are required to activate the SI phenotype of TR1.3 and W102G viruses. Collectively, these data suggest that the TR1.3 and W102G viruses induce cell fusion by the fusion-from-without pathway.

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Section: Discussionsupporting

confidence: 91%

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confidence: 99%

TR1.3 Viral Pathogenesis and Syncytium Formation Are Linked to Env-Gag Cooperation

Murphy

Gaulton

2007

J Virol

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“…Improved but presumably non-specific transduction of HSVECs was achieved by pseudotyping MLV vectors with the envelope protein of gibbon ape leukemia virus (GALV) [310]. Alternative gammaretrovirus variants, such as the neuropathogenic MLV TR1.3, which selectively infects and destroys brain capillary ECs [311], might provide platforms for highly efficient vectors in the future. Lentivirus, another member of the retrovirus family, might be better suited for endothelial gene transfer than gammaretroviruses [312,313].…”

Section: Retroviral Targeting Of Ecsmentioning

confidence: 99%

Vascular Endothelial Cells: Heterogeneity and Targeting Approaches

Hennigs

Matuszcak

Trepel³

et al. 2021

Cells

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Forming the inner layer of the vascular system, endothelial cells (ECs) facilitate a multitude of crucial physiological processes throughout the body. Vascular ECs enable the vessel wall passage of nutrients and diffusion of oxygen from the blood into adjacent cellular structures. ECs regulate vascular tone and blood coagulation as well as adhesion and transmigration of circulating cells. The multitude of EC functions is reflected by tremendous cellular diversity. Vascular ECs can form extremely tight barriers, thereby restricting the passage of xenobiotics or immune cell invasion, whereas, in other organ systems, the endothelial layer is fenestrated (e.g., glomeruli in the kidney), or discontinuous (e.g., liver sinusoids) and less dense to allow for rapid molecular exchange. ECs not only differ between organs or vascular systems, they also change along the vascular tree and specialized subpopulations of ECs can be found within the capillaries of a single organ. Molecular tools that enable selective vascular targeting are helpful to experimentally dissect the role of distinct EC populations, to improve molecular imaging and pave the way for novel treatment options for vascular diseases. This review provides an overview of endothelial diversity and highlights the most successful methods for selective targeting of distinct EC subpopulations.

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“…Murine leukemia viruses are facile tools for investigating the mechanisms of retroviral pathogenesis (26). Several correlates of increased fusion activity have been attributed to Env including increased Env expression (24,25,38,45), increased receptor affinity (12,15,54), and decreased stability of the association between Env and the viral core (27)(28)(29)(30).…”

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confidence: 99%

Linkage of Reduced Receptor Affinity and Superinfection to Pathogenesis ofTR1.3 Murine Leukemia Virus

Murphy

Chung-Landers

Honczarenko

et al. 2006

J Virol

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TR1.3 is a Friend murine leukemia virus (MLV) that induces selective syncytium induction (SI) of brain capillary endothelial cells (BCEC),The ecotropic Friend murine leukemia virus (MLV) TR1.3 was previously defined as an acutely cytopathic, syncytiuminducing (SI) variant of the noncytopathic, non-syncytium-inducing (NSI) MLV FB29. When inoculated into neonatal BALB/c mice, TR1.3 infected and caused syncytium formation in brain capillary endothelial cells (34-36). These cytopathic effects paralleled a breakdown of the blood brain barrier and hemorrhagic stroke formation. The molecular basis of both the SI phenotype and in vivo neurologic disease was previously mapped to a tryptophan (W)-to-glycine (G) substitution at amino acid position Env 102 (37). Introduction of the W102G substitution into the NSI FB29 molecular clone yielded an SI pathogenic phenotype that was identical to that seen with TR1.3. The mechanism(s) whereby mutations at Env 102 mediate SI and disease is unknown.The MLV Env consists of surface and transmembrane subdomains. Amino acids 1 to 236 of SU encompass the putative receptor binding domain (RBD) (10). Analysis of the RBD crystal structure indicates that amino acid 102 lies at the base of the predicted receptor binding pocket (13). Interaction between RBD and the ecotropic receptor murine cationic amino acid transporter 1 (mCAT-1) is essential for MLV membrane fusion and entry and for syncytium formation (1,22,53). Previous studies assessed the impact of multiple amino acid changes in Env on expression, binding, and viral entry in MLV with related genetic backgrounds (11,33). These studies showed that nonconservative substitutions of glycine or threonine for tryptophan at Env 102 altered receptor binding and transduction efficiency. However, unlike with TR1.3 and W102G, Env substitutions on these backgrounds did not result in the SI phenotype (11,33).Following MLV infection, Env downmodulates the level of available receptor on the cell surface (16,31). This process, known as superinfection interference, prevents a virally infected cell from undergoing additional rounds of infection by the same or related viruses that utilize the same cellular receptor (44,50,55). In rare circumstances, failure of MLV Env to establish superinfection interference is linked to either low Env expression levels and/or diminished mCAT-1 binding (3,4,49).Important pathological consequences can result from retroviral superinfection. Superinfection can lead to the accumulation of unintegrated linear DNA in the cytoplasm (51); by virtue of the similarity between unintegrated viral DNA and damaged DNA, this may trigger apoptosis induction in superinfected cells (9, 51). Failure to block superinfection has been linked to the in vivo cytotoxicity of mink cell focus-forming virus M13 and the neuropathogenic MLV Moloney ts1 (51, 56).Murine leukemia viruses are facile tools for investigating the mechanisms of retroviral pathogenesis (26). Several correlates of increased fusion activity have been attributed to Env including ...

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Neuropathogenic murine leukemia virus TR1.3 induces selective syncytia formation of brain capillary endothelium

Cited by 5 publications

References 31 publications

TR1.3 Viral Pathogenesis and Syncytium Formation Are Linked to Env-Gag Cooperation

TR1.3 Viral Pathogenesis and Syncytium Formation Are Linked to Env-Gag Cooperation

Vascular Endothelial Cells: Heterogeneity and Targeting Approaches

Linkage of Reduced Receptor Affinity and Superinfection to Pathogenesis ofTR1.3 Murine Leukemia Virus

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