Mouse xenotropic and polytropic leukemia viruses (XMVs and PMVs) are closely related gammaretroviruses that use the XPR1 receptor for entry. To identify amino acid residues in XPR1 important for virus entry, we tested mouse cells derived from evolutionarily divergent species for susceptibility to prototypical PMVs, XMVs, and the wild mouse isolate CasE#1. CasE#1 has a variant XMV/PMV host range, and sequence analysis of the CasE#1 env gene identifies segments related to PMVs and XMVs. Cells from the Asian mouse species Mus pahari show a unique pattern of susceptibility to these three viruses; these cells are susceptible to XMVs and CasE#1 but are resistant to PMVs, whereas NIH 3T3 cells show the reciprocal pattern, susceptibility to only PMVs. The M. pahari XPR1 gene differs from that of NIH 3T3 in the two extracellular loops The mouse gammaretroviruses can be classified into several host range groups based on receptor usage. The xenotropic and polytropic mouse virus (XMV and PMV, respectively) subgroups were initially described as distinct host range groups based on their ability to infect mouse cells (11,14,22). However, XMVs and PMVs utilize the same receptor, XPR1, and the observed host range differences are due to sequence polymorphisms in both receptor and viral envelopes. Among mouse species, three allelic variants of Xpr1 have been described: the Xpr1 n receptor found in common strains of the laboratory mouse mediates entry of PMVs but not XMVs, the Xpr1 sxv receptor variant found in many wild mouse species, such as Mus spretus, mediates entry of XMVs as well as PMVs (17), and the Xpr1 c gene of M. castaneus is defective for entry of both virus types (26). In addition to susceptibility differences due to receptor polymorphism, in some mice XPR1 is blocked by expression of endogenous interfering PMVs (the Rmcf resistance gene of DBA/2 mice) (15) or endogenous XMVs (the Rmcf2 resistance gene of M. castaneus) (25,36). Cells of many other mammalian species, such as human and mink, generally are susceptible to infection by XMVs, and many also are susceptible to PMVs (8).The XPR1 receptor has been characterized as a transmembrane protein of unknown function, although it shows homology to yeast genes involved in signal transduction and phosphate transport (4, 32, 37). XPR1 has eight predicted transmembrane domains, with the greatest sequence divergence in its fourth extracellular loop (ECL), ECL4. Mutagenesis identified two critical amino acids, K500 in ECL3 and T582 in ECL4, for XMV entry (26). Chimeras made between human XPR1 and hamster XPR1 confirm that XPR1 has two receptor determinants that independently mediate entry of XMVs in ECL3 and ECL4 and identified a receptor determinant for PMVs in the ECL4 of human XPR1 (33). The viral sequences critical for XPR1 receptor binding have not been identified, although analysis of Env chimeras indicates that the primary determinants for this specificity are in the N-terminal 118 amino acids containing the first variable domain, VRA (3), and a recent study (2) identi...
Three N-linked glycosylation sites were removed from the envelope glycoproteins of Friend, Moloney, and AKV mouse ecotropic gammaretroviruses: gs1 and gs2, in the receptor binding domain; and gs8, in a region implicated in post-binding cell fusion. Mutants were tested for their ability to infect rodent cells expressing 4 CAT-1 receptor variants. Three mutants (Mo-gs1, Mo-gs2, Fr-gs1) infect NIH 3T3 and rat XC cells, but are severely restricted in M. dunni cells and Lec8, a Chinese hamster cell line susceptible to ecotropic virus. This restriction is reproduced in ferret cells expressing M. dunni dCAT-1, but not in cells expressing NIH 3T3 mCAT-1. Virus binding assays, pseudotype assays, and use of glycosylation inhibitors further suggest that restriction is primarily due to receptor polymorphism and, in M. dunni cells, to glycosylation of cellular proteins. Virus envelope glycan size or type does not affect infectivity. Thus, host range variation due to N-glycan deletion is receptor variant-specific, cell specific, virus type-specific, and glycan site-specific.
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