Evolution of different antiviral strategies in wild mouse populations exposed to different gammaretroviruses

•Wild mice carrying XP-MLVs rarely develop virus-induced disease.•Different antiviral host factors are found in mice with X-MLVs and P-MLVs.•Mice with X-MLVs have defective or blocked receptors and a restrictive APOBEC3.•Mice with P-MLVs have a permissive receptor, a weaker APOBEC3, but make no virus.

Laboratory mice carry three host range groups of gammaretroviruses all of which are linked to leukemia induction. Although polytropic mouse leukemia viruses (P-MLVs) are generally recognized as the proximate cause of MLV-induced leukemias in laboratory mice, wild mice that carry only endogenous P-MLVs do not produce infectious virus and are not prone to disease; these mice carry the permissive XPR1 retroviral receptor and an attenuated variant of the retroviral restriction factor, APOBEC3. In contrast, Eurasian mice carrying ecotropic and xenotropic MLVs have evolved multiple restrictive XPR1 variants, other factors that interfere with MLV entry, and more effectively antiviral variants of APOBEC3. These different antiviral restrictions in Mus musculus subspecies suggest that the different virus types found in these natural populations may pose different but largely uncharacterized survival risks in their host subspecies.