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

Abstract

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 ...

An Equine Infectious Anemia Virus Variant Superinfects Cells through Novel Receptor Interactions

“…Some superinfecting strains of retroviruses display poor affinity for their receptors (19). Poor receptor affinity can prevent adequate receptor masking, permitting superinfection.…”

“…In some superinfecting scenarios, a reduction of viral envelope-receptor affinity prevents efficient superinfection resistance, thereby allowing superinfection to occur (9,19). One estimate of envelope-receptor affinity is the rapidity of virion binding to the cells.…”

“…However, a number of superinfecting strains have been described, and these variant viruses have evolved a number of different mechanisms to evade superinfection resistance. Superinfection can occur when low-affinity interactions between the viral glycoprotein and receptor do not adequately mask or downregulate the receptor (9,19). Superinfection can also occur when viruses utilize overlapping domains of the same receptor.…”

Unique N-Linked Glycosylation of CasBrE Env Influences Its Stability, Processing, and Viral Infectivity but Not Its Neurotoxicity

“…However, a subset of these WTL glycosylation site mutants, such as ⌬gs*.1, gs3.1 and ⌬gs*.1, gs5.3 viruses, showed small, contiguous, and defective foci, suggesting that the changes affected replication or cell-to cell spread in M. dunni cultures. Perhaps more surprisingly, WTL viruses harboring the gs3.6 mutation, either alone or in combination with other mutations, generated fusogenic foci, suggesting that this structural motif decreased affinity for the ecotropic receptor in a way analogous to those of other acutely cytopathic MLVs, such as Spl574, F-S, and TR1.3 (33)(34)(35)(36)(37)(38).…”

“…1A). The fusogenic phenotype of TR1.3 has been attributed to reduced binding affinity for mCAT-1 and cooperative interactions with Gag (36,37). However, for the Moloney MLV in NIH 3T3 cells, it has been shown that the fusogenic effect of Gly is suppressed by the restrictive Env R peptide (labeled the fusion trigger in Fig.…”