Polymorphisms of the cell surface receptor control mouse susceptibilities to xenotropic and polytropic leukemia viruses

The differential susceptibilities of mouse strains to xenotropic and polytr opic murine leukemia viruses (X-MLVs and P-MLVs, respectively) are poorly u nderstood but may involve multiple mechanisms. Recent evidence has demonstr ated that these viruses use a common cell surface receptor (the X-reccptor) for infection of human cells. We describe the properties of X-receptor cDN As with distinct sequences cloned from live laboratory and wild strains of mice and from hamsters and minks. Expression of these cDNAs in resistant ce lls conferred susceptibilities to the same viruses that naturally infect th e animals from which the cDNAs were derived. Thus, a laboratory mouse (NIH Swiss) X-receptor conferred susceptibility to P-MLVs but not to X-MLVs, whe reas those from humans, minks, and several wild mice (Mus dunni, SC-1 cells , and Mus spretus) mediated infections by both X-MLVs and P-MLVs, In contra st, X-receptors from the resistant mouse strain Mus castaneus and from hams ters were inactive as viral receptors, These results suggest that X-recepto r polymorphisms are a primary cause of resistances of mice to members of th e X-MLV/P-MLV family of retroviruses and are responsible for the xenotropis m of X-MLVs in laboratory mice. By site-directed mutagenesis, we substitute d sequences between the X-receptors of M, dunni and NM Swiss mice. The MII Swiss protein contains two key differences (K500E in presumptive extracellu lar loop 3 [ECL 3] and a T582 deletion in ECL 4) that are both required to block X-MLV infections. Accordingly, a single inverse mutation in the NIH S wiss protein conferred X-MLV susceptibility. Furthermore, expression of an X-MLV envelope glycoprotein in Chinese hamster ovary cells interfered effic iently with X-MLV and P-MLV infections mediated by X-receptors that contain ed K500 and/or T582 but had no effect an P-MLV infections mediated by X-rec eptors that lacked these amino acids. In contrast, moderate expression of a P-MLV (MCP247) envelope glycoprotein did not cause substantial interferenc e, suggesting that X-MLV and P-MLV glycoproteins interfere nonreciprocally with X-receptor-mediated infections. We conclude that P-MLVs have become ad apted to utilize X-receptors that lack K500 and T582, A penalty for this ad aptation is a reduced ability to interfere with superinfection. Because fai lure of interference is a hallmark of several exceptionally pathogenic retr oviruses, we propose that it contributes to P-MLV-induced diseases.