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. 2011:2011:975801.
doi: 10.1155/2011/975801. Epub 2011 Oct 23.

Naturally Occurring Polymorphisms of the Mouse Gammaretrovirus Receptors CAT-1 and XPR1 Alter Virus Tropism and Pathogenicity

Christine A Kozak  1
Affiliations

Naturally Occurring Polymorphisms of the Mouse Gammaretrovirus Receptors CAT-1 and XPR1 Alter Virus Tropism and Pathogenicity

Christine A Kozak. Adv Virol. 2011.

Abstract

Gammaretroviruses of several different host range subgroups have been isolated from laboratory mice. The ecotropic viruses infect mouse cells and rely on the host CAT-1 receptor. The xenotropic/polytropic viruses, and the related human-derived XMRV, can infect cells of other mammalian species and use the XPR1 receptor for entry. The coevolution of these viruses and their receptors in infected mouse populations provides a good example of how genetic conflicts can drive diversifying selection. Genetic and epigenetic variations in the virus envelope glycoproteins can result in altered host range and pathogenicity, and changes in the virus binding sites of the receptors are responsible for host restrictions that reduce virus entry or block it altogether. These battleground regions are marked by mutational changes that have produced 2 functionally distinct variants of the CAT-1 receptor and 5 variants of the XPR1 receptor in mice, as well as a diverse set of infectious viruses, and several endogenous retroviruses coopted by the host to interfere with entry.

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Figures

Figure 1
Figure 1
Predicted topology and sequence variation of the CAT-1 receptor for mouse ecotropic gammaretroviruses. (a) Putative topology identifies 14 predicted transmembrane domains. The third extracellular loop contains critical residues for receptor function (in red) and two N-linked glycosylation sites. (b) Sequence variation in the CAT-1 third extracellular loop. At the top are three sequence variants found in Mus with residues critical for entry in red. Virus infectivity of cells expressing these receptors is measured as the log10 titer of FFU/100 μL of viral Env pseudotypes carrying the LacZ reporter gene; ND: not done. Consensus sites for N-glycosylation are underlined. CAT-1 sequence variation is shown for mouse CAT-1 variants mCAT-1 (NIH 3T3), dCAT-1 (M. dunni), and minCAT-1 (M. minutoides). E-MLV-infected Mus species M. castaneus, M. molossinus, M. spicilegus, and M. musculus are identical to mCAT-1 in the indicated region. Also shown are CAT-1 sequences for virus-susceptible species hamster (ha), rat (r), and XC rat cells (xc) and for virus-resistant human (hu).
Figure 2
Figure 2
Structure of the FrMLV E-MLV Env gene. (a) Stick figure representation identifies the surface (SU) and transmembrane (TM) domains, the receptor binding domain (RBD) containing three variable regions (VRA, VRB, and VRC), and the proline-rich domain (PRD). Green triangles mark the N-linked glycosylation sites in SU. Vertical lines identify residues with roles in entry; the three residues in red form the binding pocket. The C-terminal segments designated C2 and loop10 have also been implicated in entry [42, 43]. (b) Surface representation of the FrMLV RBD (PDB ID 1AOL) [36], showing the location of the binding pocket (red), additional residues involved in entry (blue), and two N-linked glycosylation sites (green).
Figure 3
Figure 3
Phylogenetic tree of the Env genes of E-MLV gammaretroviruses. The tree includes laboratory mouse isolates FrMLV, MoMLV, and Rauscher MLV (RaMLV), the naturally occurring viruses AKV MLV, CasBrE, and HoMLV, and the Env gene of the Fv4 restriction gene. The three related groups are bracketed. Sequences from GenBank were aligned using ClustalW2 and used to generate neighbour-joining trees. The X-MLV NZB-9-1 was included to root the tree.
Figure 4
Figure 4
Alignment of the predicted amino acid sequences of the N-terminal portion of the Env sequences of various XP-MLVs. Included are the prototype NZB-9-1 X-MLV, the Friend FrMCF P-MLV, the wild mouse isolates CasE#1 and Cz524, and XMRV. Green blocks identify the three variable domains of the RBD and the PRD, and a blue block identifies two residues that influence species tropism [93].
Figure 5
Figure 5
Predicted topology and sequence variation of the XPR1 receptor for XP-MLVs. At the top is shown the predicted structure with eight putative transmembrane domains and 4 extracellular loops (ECLs). The center diagram shows the relative locations of the 4 ECLs in the XPR1 protein, and the bottom shows sequence variation in the two ECLs involved in virus entry. Sequence is provided for the 5 functional XPR1 variants in Mus, and the red arrows indicate the 6 residues involved in entry.
Figure 6
Figure 6
Phylogenetic tree of Mus. Blue arrows indicate the species that have acquired XP-MLV ERVs, and the subset that have predominantly X-MLVs. 4 colored boxes identify the mice carrying the 4 restrictive Xpr1 alleles; all other species carry the permissive Xpr1sxv.
Figure 7
Figure 7
Geographic distribution of Xpr1 alleles in wild mouse populations.
Figure 8
Figure 8
The entry of various XP-MLVs is affected by sequence variation in ECL3 or ECL4 suggesting that these domains form a single receptor site.
Figure 9
Figure 9
Susceptibility of various mammalian cells to XP-MLVs. Infectivity is measured as the log10 titer of FFU/100 μL of viral Env pseudotypes carrying the LacZ reporter. Log10 titer: +++, >3; ++, 2-3; +, 1-2. Infectivity of Chinese hamster cells can be increased by treatment with glycosylation inhibitors. Amino acid sequences are shown for the receptor determining regions of ECL3 and ECL4.
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