The mouse "xenotropic" gammaretroviruses and their XPR1 receptor

Abstract

The xenotropic/polytropic subgroup of mouse leukemia viruses (MLVs) all rely on the XPR1 receptor for entry, but these viruses vary in tropism, distribution among wild and laboratory mice, pathogenicity, strategies used for transmission, and sensitivity to host restriction factors. Most, but not all, isolates have typical xenotropic or polytropic host range, and these two MLV tropism types have now been detected in humans as viral sequences or as infectious virus, termed XMRV, or xenotropic murine leukemia virus-related virus. The mouse xenotropic MLVs (X-MLVs) were originally defined by their inability to infect cells of their natural mouse hosts. It is now clear, however, that X-MLVs actually have the broadest host range of the MLVs. Nearly all nonrodent mammals are susceptible to X-MLVs, and all species of wild mice and several common strains of laboratory mice are X-MLV susceptible. The polytropic MLVs, named for their apparent broad host range, show a more limited host range than the X-MLVs in that they fail to infect cells of many mouse species as well as many nonrodent mammals. The co-evolution of these viruses with their receptor and other host factors that affect their replication has produced a heterogeneous group of viruses capable of inducing various diseases, as well as endogenized viral genomes, some of which have been domesticated by their hosts to serve in antiviral defense.

Figure 1

Distribution of Xpr1 variants and endogenous X/P-MLV env genes in the genus Mus. The 4 subgenera originated about 7.5 million years ago (MYA). Red arrows and brackets mark the distribution of the 5 functionally defined Xpr1 alleles among Mus species and strains. The house mouse species are indicated by a bracket, and the specific MLV ERV env types found in Mus are listed on the right. The tree is adapted from the synthetic trees developed by Guenet and others [63,64,211].

Figure 2

Geographic distribution of the 4 house mouse species of Mus in Eurasia. The three blue blocks show the distribution of species carrying primarily Xmvs, and the yellow block marks the range of the species carrying M/Pmvs. The blue line is the Yangtze River which roughly coincides with the transition between M. castaneus and musculus [66], and the red line represents the well-studied hybrid zone separating musculus and domesticus [211]. Infectious viruses of the indicated types were isolated from mice trapped at sites indicated with arrows; not shown: the X/P-MLV virus CasE#1 isolated from a California wild mouse.

Figure 3

Southern blot analysis of genomic DNAs of house mouse species using env-specific hybridization probes. At the bottom is a diagram of the MLV env showing the position of the ~120 bp hybridization probes [33,71].

Figure 4

Five functional variants of Xpr1 in Mus. Susceptibility to 4 host range X/P-MLV variants was determined using virus pseudotypes carrying the LacZ reporter gene [101].

Figure 5

Putative transmembrane structure of XPR1 and locations of the 6 residues responsible for receptor function. XPR1 has 4 putative extracellular loops (top) indicated as yellow bars in the mRNA. Codon positions for residues involved in entry are marked with arrows, and residues at these sites are shown for the 5 Mus alleles. "-" represents a deletion.

Figure 6

Distribution of Xpr1^sxv and Xpr1^m in mice trapped in various sites in Europe. The red line represents the 20 km-wide hybrid zone separating the ranges of M. domesticus and M. musculus [212]. Symbols indicate the trapping sites of each sequenced sample [101].