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Published in final edited form as: Virology. 2016 Jul 15;497:53–58. doi: 10.1016/j.virol.2016.06.026

Permissive XPR1 gammaretrovirus receptors in four mammalian species are functionally distinct in interference tests

Qingping Liu 1, Yuhe Yan 1,1, Christine A Kozak 1,*
PMCID: PMC5026577  NIHMSID: NIHMS803457  PMID: 27423269

Abstract

Xenotropic/polytropic mouse leukemia viruses (X/P-MLVs) use the XPR1 gammaretrovirus receptor for entry. X/P-MLV host range is defined by usage of naturally occurring restrictive XPR1 receptors, and is governed by polymorphisms in the virus envelope glycoprotein and in XPR1. Here, we examined receptors of four mammalian species permissive to all X/P-MLVs (Mus dunni, human, rabbit, mink). Interference assays showed the four to be functionally distinct. Preinfection with X-MLVs consistently blocked all nine XPR1-dependent viruses, while preinfection with P-MLVs and wild mouse X/P-MLVs produced distinctive interference patterns in the four cells. These patterns indicate shared usage of independent, but not always fully functional, receptor sites. XPR1 sequence comparisons identified candidate sites in receptor-determining regions that correlate with some interference patterns. The evolutionary record suggests that the X/P-MLV tropism variants evolved to adapt to host receptor polymorphisms, to circumvent blocks by competing viruses or to avoid host-encoded envelope glycoproteins acquired for defense.

Keywords: Mouse gammaretroviruses, mouse leukemia viruses, XPR1 retrovirus receptor, gammaretrovirus interference

Introduction

The mouse gammaretroviruses are subgrouped by host range and interference properties that are determined by receptor usage. The ecotropic mouse leukemia viruses (E-MLVs) infect only rodent cells and use the CAT-1 receptor encoded by Slc7a1 (Albritton et al., 1989). Viruses that use the XPR1 receptor (Battini et al., 1999; Tailor et al., 1999; Yang et al., 1999) include polytropic MLVs (P-MLVs) which infect laboratory mice and other mammals, xenotropic MLVs (X-MLVs) which are restricted in most inbred strains of laboratory mice, and viruses not clearly in either host range subgroup; these XPR1-dependent viruses are collectively termed X/P-MLVs. The wild mouse amphotropic MLV (A-MLV) uses the PiT-2 receptor encoded by Slc20a2 (Miller et al., 1994).

Cells of the various inbred strains, wild mouse species and other mammalian species differ in their susceptibility to MLVs, and some of these resistance phenotypes result from interference with the virus-receptor interaction. These entry blocks are of two types. First, restriction can result from receptor polymorphisms that alter interaction with the viral envelope (env). For the E-MLVs, such polymorphisms are found in a wild mouse variant of CAT-1 responsible for resistance to Moloney E-MLV (Eiden et al., 1993), in a hamster CAT-1 variant that restricts all E-MLVs except for some variants of Friend E-MLV (Masuda et al., 1996), and in the CAT-1 receptors of non-rodent mammalian species, all of which restrict E-MLV infection. For the X/P-MLV XPR1 receptor, there are at least six functional variants in Mus, five of which restrict one or more X/P-MLV isolates (Bamunusinghe et al., 2013; Yan et al., 2010). Virtually all nonrodent XPR1s can function as virus receptors, allowing entry of some or all X/P-MLVs (Kozak, 2010).

The second set of host factors that can inhibit MLV entry are found only in mice. These restriction factors are Env glycoproteins encoded by endogenous retroviruses (ERVs), which are MLV DNA copies inserted into host genomes during past infections. The Env glycoproteins produced by specific ERVs like Fv4 and Rmcf are thought to block virus entry by interference (Bassin et al., 1982; Hartley et al., 1983; Ikeda et al., 1985), and in the case of Fv4, there is a mutation in the fusion domain of the transmembrane subunit of the Env polyprotein that prevents infection by virions that incorporate the Fv4 Env (Taylor et al., 2001). Such restrictive Env-encoding ERVs are also found in cats, chickens and sheep (McDougall et al., 1994; Robinson et al., 1981; Spencer et al., 2003), suggesting this is a common host strategy for virus restriction.

In Mus, restrictive XPR1 variants and Env glycoproteins evolved in taxa exposed to MLVs, and the viruses found in these mice are polymorphic in the receptor binding domain (RBD) of their viral env genes (reviewed in (Kozak, 2013)). These host and virus phenotypic variants likely represent co-evolutionary adaptations resulting from a host-virus “arms race” in which the development of the host survival strategies that block entry coincided with the appearance of X/P-MLV host range variants. These env variants are thus likely to represent adaptations to XPR1 receptor polymorphisms, or may have evolved to circumvent blocks due to competing viruses or host-encoded Env glycoproteins.

Analysis of the restrictive receptor variants found in Mus identified six receptor critical residues in two putative extracellular loops, ECL3 and ECL4 (Marin et al., 1999; Yan et al., 2007; Yan et al., 2009; Yan et al., 2010). Mutations at the two sites most critical for X-MLV entry were also found to disable XPR1 receptor function in bird species exposed to X/P-MLVs (Martin et al., 2013). In the present study, we shifted our focus to the permissive XPR1 receptors that mediate entry of all X/P-MLVs. Most Mus species and some laboratory strains carry the permissive Xpr1sxv allele (Baliji et al., 2010; Yan et al., 2010), and there are other XPR1 receptors in various non-rodent mammalian species that are fully permissive despite considerable sequence variation in the receptor-determining regions (Yan et al., 2010). If competition for XPR1 by multiple viruses or ERV-encoded Env is a driving factor in receptor-virus co-evolution, then interference assays might uncover novel receptor usage patterns not identified in studies of restrictive receptors. In this study, we used permissive cells from four mammalian species (mouse, human, mink, rabbit) in virus interference assays to determine if nine X/P-MLV isolates use the same or different receptor determinants in these four polymorphic, but fully permissive receptors. Results show that X-MLVs effectively interfere with all XPR1-dependent viruses in all four cells, while three P-MLVs and two wild mouse isolates, CasE#1 and Cz524, produce distinctive species-specific interference profiles that can, in some cases, be correlated to specific receptor sequence variations.

Materials and Methods

Viruses

Five laboratory mouse X/P-MLVs isolates were obtained from J. Hartley (NIAID, Bethesda, MD): the X-MLVs NZB-9-1 and AKR6, and the mink cell focus-inducing (MCF) P-MLVs MCF247, Friend MCF (FrMCF), and Moloney MCF (MoMCF). XMRV X-MLV (xenotropic mouse-related virus) (Dong et al., 2007), was provided by R. Silverman (Cleveland Clinic, Cleveland, OH).

MLVs obtained from wild mice include CAST-X X-MLV isolated from a CAST/EiJ mouse (M. m. castaneus) (Yan et al., 2007) and Cz524 X/P-MLV isolated from a CZECHII/EiJ mouse (M. m. musculus) (Yan et al., 2009). CasE#1 X/P-MLV and the 4070A amphotropic MLV (A-MLV) were both isolated from mice from Lake Casitas, CA (Cloyd et al., 1985; Hartley and Rowe, 1976) and both were obtained from J. Hartley (NIAID, Bethesda, MD).

Pseudotype and interference assays

Retrovirus stocks carrying the LacZ reporter were generated for the various MLVs by virus infection of GP2-293 cells transfected with pCL-MFG-LacZ (Yan et al., 2009). Pseudovirus susceptibility was scored in cells infected with 50 μl of 10-fold dilutions of pseudotype virus stocks in the presence of 4–8 μg/ml polybrene. One day after infection, cells were fixed with 0.4% glutaraldehyde and assayed for β-galactosidase activity using as substrate 5-bromo-4-chloro-3-indolyl-β-D-galactopyranoside (X-Gal, 2 mg/ml; ICN Biomedicals, Aurora, Ohio).

Interference with X/P-MLV pseudovirus infection was tested in five cell lines chronically infected with various X/P-MLVs or A-MLV: M. dunni obtained from M. Lander (NIAID, Bethesda, MD) (Lander and Chattopadhyay, 1984), human 293 (ATCC CRL-1573), mink lung Mv-1-Lu (CCL-64), rabbit SIRC (CCL-60), and a mouse cell line developed from cultured tail biopsy tissue from Mus pahari, obtained from J. Rogers (Baylor College of Medicine, Houston, TX). Chronically infected cultures were established by infecting subconfluent cultures with MLVs at MOI 1, and passing the cells 3–8 times. Cells were used in interference assays when the infected culture could not be infected with its cognate pseudovirus and virus protein expression was confirmed by western analysis. Interference was measured as the percent ratio of the pseudovirus titer in virus-infected cells divided by the titer in uninfected control cells.

Cell lysates from infected cultures were tested for viral proteins by western analysis on NuPage: 4–12% Bis-Tris gels(Invitrogen) or on sodium dodecyl sulfate polyacrylamide gels (8 or 10%). Immunoblot analysis used goat polyclonal antibodies against Rauscher MLV gp70 Env (79S-603) and p30 CAgag (79S-804) (Viromed Biosafety Laboratories, Camden, NJ) which were then detected with HRP-conjugated anti-goat secondary antibody (Santa Cruz Biotechnology, Santa Cruz, CA).

Results

Viral interference in 4 permissive cell lines

Cells of four mammalian species (mink, human, rabbit, M. dunni mouse) are susceptible to infection by all XPR1-dependent viruses (Kozak, 2010). The XPR1 receptors in these four cells show significant sequence differences in the receptor-determining regions that are found in two of its four putative extracellular loops, ECL3 and ECL4 (Fig. 1A). These two regions independently mediate entry of X-MLVs, and both must be mutated to block infection (Marin et al., 1999). In ECL4, the human and rabbit XPR1 proteins are identical but differ from the mink and mouse variants. The receptor-determining region at the C-terminal end of ECL3 is identical in mink, human and rabbit but different in the mouse. The four receptors all differ from one another in the N-terminal end of ECL3, a region implicated in XPR1 receptor function in birds (Martin et al., 2013).

Figure 1.

Figure 1

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Alignment of putative protein sequences of the receptor determining regions of XPR1 from 5 mammalian species, and the Env RBD of 9 X/P-MLVs. (A) Putative XPR1 extracellular loops ECL3 and ECL4 are marked in red and triangles identify six residues involved in receptor function. Green and blue letters mark replacement mutations unique to rabbit and M. dunni, respectively. Arrows mark sites under positive selection in rodents (blue) (Yan et al., 2010) and birds (black) (Martin et al., 2013). (B) Blue letters mark VRA, VRB and 2 residues known to affect entry (Bahrami et al., 2004). The stick figure shows the position of RBD in env. GenBank accession numbers: NZB (K02730), CAST-X (KU324803), XMRV (EF185282), AKR6 (DQ199948), CasE#1 (KU324802), Cz524 (KU324804), FrMCF (GQ420673), MCF247 (K00526), MoMCF (J02254).

Nine X/P-MLVs were chosen for interference testing because they represent widely used prototypes, show different host range tropisms, and/or show sequence differences in env. Thus, while none of the 4 X-MLVs infect Chinese hamster cells, two, CAST-X and NZB, can infect glycosylation-defective Lec8 hamster cells (Yan et al., 2009). FrMCF and MoMCF P-MLVs differ in their ability to infect rat cells (Cloyd et al., 1985; Yan et al., 2009). The wild mouse isolates CasE#1 and Cz524 infect different subsets of mammalian cells than do prototypical X- or P-MLVs (Cloyd et al., 1985; Kozak, 2010). These nine X/P-MLVs are significantly different in their Env RBDs (Fig. 1B), especially in the VRA variable region implicated in receptor choice (Battini et al., 1992). Outside of VRA, RBD sites 183 and 184 affect the ability of some X/P-MLVs to infect mink and human cells (Bahrami et al., 2004), and other Env regions or sites outside RBD have been implicated in post-binding virus-cell fusion (Cote et al., 2012; Lavillette et al., 2001; Zavorotinskaya and Albritton, 1999).

Cultures of human 293 cells, mink lung, rabbit SIRC and Mus dunni cells chronically infected with various X/P-MLVs were superinfected with LacZ pseudotypes of the same set of viruses to test for interference (Fig. 2). Amphotropic MLV, which infects all 4 of these same cells using the PiT2 receptor, was used as the control. Chronically infected cells were not produced for all virus-cell combinations, for example, human 293 cells were efficiently infected by XMRV pseudotypes, but chronically infected 293 cells could not be established for XMRV, as has been reported by others (Rodriguez and Goff, 2010).

Figure 2.

Figure 2

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Interference of X/P-MLV pseudovirus infection in cells of 4 mammalian species chronically infected with various MLVs. Numbers represent the average percent of the titer in infected cells/titer in control cells; infected cells were tested 2–8 times. High numbers indicate little to no interference; significant interference is marked by titer reductions of 100-fold, indicated as <1.

In interference assays, the superinfecting virus is blocked in cells preinfected with any virus using the same receptor determinant, and viral interference is typically defined by titer reductions of 100-fold or more (Chesebro and Wehrly, 1985; Cloyd et al., 1985; Rein, 1982). For XPR1, interference assays are complicated by the fact that X-MLVs can use two independent XPR1 receptor determinants found in different putative extracellular loops, both of which are not necessarily used by other X/P-MLVs (Marin et al., 1999; Yan et al., 2010). Differential usage of these two receptor determinants results in nonreciprocal interference patterns as has been reported between X-MLVs and the P-MLVs and between X-MLVs and CasE#1 (Cloyd et al., 1985; Marin et al., 1999; Miller and Wolgamot, 1997; Van Hoeven and Miller, 2005). In cells from laboratory mice that carry the X-MLV restrictive Xpr1n variant, X-MLV does not interfere with P-MLVs, supporting the idea that X-MLV has no affinity for either of the XPR1 receptor determinants in Xpr1n (Rein and Schultz, 1984). Also, as seen in Figure 2, many combinations of viruses using the XPR1 receptor produce a partial reduction of superinfection (2–10 fold).

In all four cells, the X-MLVs block infection by all other X/P-MLVs (Fig. 2). Consistent with previous observations (Miller and Wolgamot, 1997), all 3 P-MLVs tested here (FrMCF, MoMCF, MCF247) blocked P-MLV pseudovirus infection but did not block X-MLVs indicating that all 4 of these receptors carry at least one determinant for X-MLVs and one shared by X- and P-MLVs.

For other virus/pseudovirus combinations, there are clear differences in interference patterns that are cell- and virus-specific (Fig. 2). Thus, the ability of P-MLVs to block infection by CasE#1 and Cz524 is different in all four cells. In SIRC cells, P-MLVs block both wild mouse viruses, whereas in human 293 cells, P-MLVs block CasE#1 but not Cz524, and in M. dunni cells, they block Cz524 but not CasE#1. P-MLV-infected mink cells show a fourth restriction pattern in which different P-MLVs show different interference patterns; cells pre-infected with FrMCF and MoMCF block both wild mouse viruses while MCF247-infected cells block neither.

Preinfection with the two wild mouse viruses also produced different nonreciprocal interference patterns in these cells. Both viruses fail to block X-MLV pseudovirus infection in 293 cells, and in mink cells fail to block X-MLVs with the exception of XMRV which is blocked only by Cz524. In contrast, all X-MLVs are blocked by Cz524 but not CasE#1 in SIRC cells, while in M. dunni, X-MLVs are blocked by CasE#1 but not Cz524. (Fig. 2).

These results show that XPR1-dependent MLVs show different interference patterns in cells that are otherwise indistinguishable by their permissiveness to infection by all X/P-MLVs. This indicates that the sequence variants among these receptors have phenotypic consequences, and show that naturally occurring permissive as well as restrictive receptors are differentially recognized by this panel of X/P-MLVs.

Interference in Mus pahari cells

Because of the dissimilar interference patterns in these permissive cells, we also looked at interference patterns in cells of M. pahari, a Mus species with a restrictive receptor functional only for X-MLVs and CasE#1 (Yan et al., 2007). Interference assays showed that these two viruses show fully reciprocal interference with each other in these cells and therefore rely on the same receptor determinant in this partially functional mouse receptor (Fig. 3). CasE#1 shows a similar fully reciprocal interference with X-MLVs in only one of the four tested permissive cells, M. dunni, while producing nonreciprocal interference in SIRC, human and mink cells (Fig. 2), as well as in rat cells (Cloyd et al., 1985). This can be best explained by concluding that all of these permissive cells carry receptors that have both functional X-MLV receptor determinants, but CasE#1 is able to use both X-MLV receptor determinants only in M. dunni. In contrast, M. pahari has only a single functional receptor determinant that is used by both CasE#1 and X-MLVs. The M. pahari XPR1 sequence differs from M. dunni in ECL3 and ECL4, and while mutational analysis suggests that CasE#1 and X-MLVs rely on the M. pahari ECL4 determinant (Yan et al., 2007), this may not be the case for the other XPR1s which have multiple sequence variations in both ECL3 and ECL4 (Fig. 1A).

Figure 3.

Figure 3

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Interference between X-MLVs and CasE#1 in M. pahari cells. Numbers represent the average percent of the titer in infected cells/titer in control cells; infected cells were tested 2–5 times. High numbers indicate little to no interference; significant interference is marked by titer reductions of 100-fold (<1).

Discussion

The co-evolution of mouse leukemia viruses and their mouse hosts is marked by cycles of mutational adaptations and counter-adaptations at their sites of interaction. This molecular “arms race” has resulted in phenotypically distinct restrictive variants of the XPR1 gammaretrovirus receptor for X/P-MLVs in virus-infected wild mice, the appearance of host range MLV variants with different receptor specificities, and the acquisition of host-encoded viral Env glycoproteins that block virus infection (Kozak, 2010). Here we used virus interference assays with cells of four mammalian species that are permissive to all X/P-MLVs to describe new species-specific interference phenotypes that uncover novel patterns of receptor usage.

Results support three general observations: First, some combinations of X/P-MLVs produce significant reciprocal cross-interference thus identifying virus pairs that use the same entry determinants in specific XPR1 receptors (E.g., X-MLVs and Cz524 in SIRC, X-MLVs and CasE#1 in M. dunni). Second, some X/P-MLVs can block some but not all XPR1-dependent MLVs demonstrating that interference is due to receptor masking rather than receptor downregulation, as shown for other receptors (Liu and Eiden, 2011). Third, some virus/pseudovirus combinations produce partial titer reductions. This was observed in many P-MLV/wild mouse virus pairings, but has also been described among P-MLVs (Marin et al., 1999). This partial interference may be due to weak affinity for shared receptor determinants or to overlapping or adjacent binding sites that are partially blocked by nearby virus attachment. The failure of closely related or identical viruses to establish superinfection immunity is a common property of various pathogenic retroviruses including P-MLVs that are capable of cytopathic killing (Cheng-Mayer et al., 1988; Li and Fan, 1990; Temin, 1988; Yoshimura et al., 2001). It is unlikely that these interference properties are due to involvement of a second receptor, as susceptibility phenotypes are consistently reproduced in transfected hamster cells and through analysis of mutated receptors. While there is evidence that highly restrictive BHK cells may uniquely lack a cofactor necessary for infection by some X/P-MLVs, this factor has not been identified or implicated in other cells (Xu and Eiden, 2011).

The molecular genetic basis for some of these different interference patterns in the four polymorphic receptors can be inferred from sequence comparisons of receptors with shared phenotypes. Thus, Cz524 and X-MLVs interfere with all X/P-MLVs in SIRC but not in the other three cells. Rabbit XPR1 differs from the other three at five sites all clustered in the N-terminal end of ECL3 (Fig. 1A). This segment of ECL3 has been linked to receptor function in avian XPR1 but has not been assessed in mammalian XPR1s (Martin et al., 2013). However, one of these five sites (434) has been shown to be under under positive selection in rodents (Yan et al., 2010) and 2 other sites in this region are under positive selection in rodent (position 442) and in the avian XPR1 gene (position 424) (Martin et al., 2013). Positive selection in host genes that interact with viruses is suggestive of genetic conflicts that can mark sites involved in antiviral activity.

Among the permissive cells, preinfection with CasE#1 produces X-MLV-like interference only in dunni cells. Substitutions that distinguish the dunni XPR1 from the other three permissive orthologs are found at seven sites in the receptor determining ECLs. Three are in ECL4 and four are in the receptor determining region in the C-terminal end of ECL3 (Fig. 1A), one of which (position 508) was previously shown to influence receptor function (Yan et al., 2009). All three of the ECL3 sites and two of the ECL4 sites are under positive selection in rodents (Yan et al., 2010). Also, M. pahari, like M. dunni, shows similar reciprocal interference between these viruses, and its XPR1 shares the dunni residues at five of these seven sites.

Examination of the X/P-MLV RBD for phenotype-linked substitutions is less informative due to the larger number of differences, and because there are few shared variations among viruses with similar interference properties. The involvement of the env VRA in receptor choice has been established (Battini et al., 1992), and crystal structure of the ecotropic RBD indicates that the VRA and VRB regions jut out from the apex of the Env RBD where they are well-situated for virus contact (Fass et al., 1997). The most obvious VRA sequence difference among the X/P-MLVs is deletion of three residues in Cz524 and four in the X-MLVs relative to the P-MLVs; this region also has host-range linked adjacent substitutions at positions 75 and 76 which is TR in the P-MLVs and CasE#1, but is LY in X-MLVs and Cz524 (Fig. 1B). None of these sequence differences have been formally evaluated for involvement in entry.

The three P-MLVs used here differ from one another in interference properties in the four cell lines, and in their ability to infect cells of other species (Cloyd et al., 1985). These phenotypes may result from the nine replacement mutations in RBD or the presence of a nine residue deletion in the proline rich region of Env in FrMCF, a region implicated in virus entry for another gammaretrovirus, the porcine endogenous retrovirus (Argaw and Wilson, 2012).

The fact that four permissive XPR1 receptors are distinguishable in interference assays suggests that the plasticity of the MLV-XPR1 interaction is more extensive than defined by tropism. This observed plasticity was not molded by encounters with the receptors analyzed here. X/P-MLVs are not known to infect the three non-rodent species carrying these permissive XPR1s (human, rabbit, mink), and in Mus, the M. dunni receptor allele is ancestral to the restrictive receptors and predates exposure of Mus to infectious X/P-MLVs (Yan et al., 2010). Instead this env plasticity likely evolved as adaptations to the known (and undiscovered) receptor polymorphisms carried by the virus-infected subspecies of Mus musculus, and to competing XPR1-dependent viruses widespread in house mouse subspecies (Bamunusinghe et al., 2016; Tomonaga and Coffin, 1998).

Viruses can alter their receptor usage by drastic measures like env acquisition or receptor switching. The mouse gammaretroviruses, however, have limited options for receptor switching as this retrovirus family is uniquely adapted to the use of multipass transmembrane proteins that function as transporters (Tailor et al., 2003), so switching possibilities appear to be restricted to a set of structurally similar transmembrane transport proteins. For the X/P-MLVs, this switching restriction has resulted in adaptations to alternative sites on the same protein. The fact that Mus carries a rich trove of uncharacterized MLVs suggests that the full range of this host/virus co-evolutionary variation has not been fully described.

Highlights.

  • Four polymorphic mammalian XPR1 gammaretrovirus receptors are fully permissive.

  • The four receptors are functionally distinct in interference assays.

  • Interference patterns reflect differential use of independent XPR1 receptor sites.

  • Sequence comparisons identify candidate residues linked to interference phenotypes.

  • These novel patterns of receptor usage derive from virus/host co-evolution.

Acknowledgments

This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, Bethesda, MD. We thank Venkat Yedavalli for assistance with figure preparation.

Footnotes

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