Common Inbred Strains of the Laboratory Mouse That Are Susceptible to Infection by Mouse Xenotropic Gammaretroviruses and the Human-Derived Retrovirus XMRV

Xenotropic mouse gammaretroviruses were first isolated by Levy and Pincus from the NZB strain of laboratory mice (25). The virus was termed xenotropic because of its inability to infect cells of the various inbred mouse strains, although it could infect rat cells. Subsequent studies isolated this virus type from additional strains of inbred and outbred laboratory mice (23) and showed that these viruses are infectious for cells of multiple mammalian species (24, 33). The various inbred strains of laboratory mice carry up to 15 endogenous proviruses related to infectious xenotropic mouse leukemia viruses (X-MLVs) (8, 34), and some of these germ line X-MLV proviruses, or XMVs, are capable of producing infectious virus or viral proteins (reviewed in reference 40). These inbred mouse strains differ in their abilities to produce infectious X-MLVs because of the different XMVs that they carry and because of the presence of regulatory genes that alter virus expression and spread. Two strains, F/St and NZB, have a “high-virus” phenotype; that is, they are viremic with X-MLVs from an early age, and virus can readily be isolated from cells and tissues of these strains (6, 25, 31). A second and larger set of inbred strains, which includes common strains such as C57BL and BALB/c, carry XMVs that produce virus after chemical or immunological stimulation (1, 9, 27, 38). A third set of strains, including Swiss strain-derived mice and strains such as A and C3H, are not or are rarely capable of producing infectious X-MLV. Four active XMVs have been identified in the strains that can produce infectious virus. Two of these proviruses are found in NZB mice (6), a third provirus, termed Bxv1, is found in several common inbred strains (8, 18, 19), and the fourth is found along with the Bxv1 provirus in MA/My mice (16). Only one of these proviruses, Bxv1, has been mapped in the mouse genome; it has been mapped to a position on distal chromosome 1 (Chr 1), where it was first located by conventional linkage analysis of chemically inducible virus production (18). The provirus at this locus was subsequently identified by Southern blotting of somatic cell hybrids and recombinant inbred mouse strains (11, 8). The Bxv1 provirus (also termed Xmv43) is present in the sequenced C57BL mouse genome and maps at 179 MB on Chr 1 (12). This provirus is biologically important for two reasons: not only does Bxv1 reliably produce virus in response to specific inducers (18, 19), but it is also involved in virus-induced leukemias. These diseases are associated with the generation of recombinant leukemogenic polytropic MLVs (P-MLVs), and the Bxv1 provirus has been identified as the source of the long terminal repeat sequences of these pathogenic recombinants (11, 41). The presence of multiple endogenous XMVs in mice that are not susceptible to X-MLV infection can be explained by looking at the wild mouse progenitors of these laboratory strains. The common laboratory strains represent a mosaic of three house mouse species: Mus domesticus, Mus castaneus, and Mus musculus (49). Two of these 3 species carry XMVs (17, 43), and the 3 species carry 3 different alleles of the XPR1 receptor used for entry by X-MLVs, all 3 of which are permissive for X-MLVs (28, 47, 48). In contrast, the XPR1 receptor gene originally cloned from NIH 3T3 cells is not permissive for X-MLV entry (2, 42, 50). This suggests that XMVs were originally acquired by X-MLV-susceptible wild mice and that the receptor variants permissive for this virus were lost in the fancy mouse breeding stocks used to generate laboratory strains. There are hundreds of strains of laboratory mice. While it is generally recognized that these strains are less genetically diverse than wild Mus species, it is clear that there are distinct lineages of laboratory strains that can be traced to different fancy mouse and wild mouse progenitors. Few of the hundreds of mouse strains have actually been tested for X-MLV susceptibility, and the observations that X-MLV susceptibility is widespread among wild mice and that these inbred strain lineages represent different mosaics of wild mouse species (49) raised the possibility that X-MLV-permissive Xpr1 alleles might have been captured in some of these strains. In this study, we screened inbred strains of laboratory mice for the presence of known and novel variants of the Xpr1 receptor, with the goal of identifying strains susceptible to X-MLV infection. We also identified the inbred strains carrying the inducible Bxv1 provirus and identified the origin of this provirus in the Japanese house mouse species Mus molossinus. The permissive sxv allele of Xpr1 (Xpr1sxv) was identified in 7 inbred strains, including the high-virus, Bxv1-positive F/St strain. We also demonstrate that cells from laboratory mouse strains carrying Xpr1sxv can be efficiently infected with XMRV and X-MLVs.