Abstract
The classical laboratory mouse strains are genetic mosaics of three Mus musculus subspecies that occupy distinct regions of Eurasia. These strains and subspecies carry infectious and endogenous mouse leukemia viruses (MLVs) that can be pathogenic and mutagenic. MLVs evolved in concert with restrictive host factors with some under positive selection, including the XPR1 receptor for xenotropic/polytropic MLVs (X/P-MLVs) and the post-entry restriction factor Fv1. Since positive selection marks host-pathogen genetic conflicts, we examined MLVs for counter-adaptations at sites that interact with XPR1, Fv1, and the CAT1 receptor for ecotropic MLVs (E-MLVs). Results describe different co-adaptive evolutionary paths within the ranges occupied by these virus-infected subspecies. The interface of CAT1, and the otherwise variable E-MLV envelopes, is highly conserved; antiviral protection is afforded by the Fv4 restriction factor. XPR1 and X/P-MLVs variants show coordinate geographic distributions, with receptor critical sites in envelope, under positive selection but with little variation in envelope and XPR1 in mice carrying P-ERVs. The major Fv1 target in the viral capsid is under positive selection, and the distribution of Fv1 alleles is subspecies-correlated. These data document adaptive, spatial and temporal, co-evolutionary trajectories at the critical interfaces of MLVs and the host factors that restrict their replication.
Highlights
The classical inbred strains of laboratory mice carry mouse leukemia viruses (MLVs) of three host range groups: ecotropic, xenotropic, and polytropic (E-MLVs, X-MLVs, PMLVs) [1,2,3]
Despite extensive sequence variation in the ecotropic MLVs (E-MLVs) receptor binding domains (RBDs), these MLVs show no adaptive changes in the receptor binding pocket nor is there variation in the receptor critical region of the M. musculus CAT1 suggesting that other factors, such as the Fv4 restriction gene in some virus-infected populations, help mitigate the consequences of infection
Limiting the analysis to mice and hamsters, which are generally susceptible to E-MLV infection, identifies only five sites under positive selection, none of which is in ECL3
Summary
The classical inbred strains of laboratory mice carry mouse leukemia viruses (MLVs) of three host range groups: ecotropic, xenotropic, and polytropic (E-MLVs, X-MLVs, PMLVs) [1,2,3] These gammaretroviruses are found either as infectious retroviruses (XRVs) or as endogenous retroviruses (ERVs), which are viral DNA copies inserted into host chromosomes during past infections. The various laboratory strains and wild mouse subspecies differ in their susceptibility to MLVs, and to virus-induced disease, due to host factors that can inhibit virus replication at different stages of the virus life cycle, including entry, reverse transcription, transport to the nucleus, transcription, and budding [8] Some of these factors have no known function other than virus restriction, while others serve important host functions that facilitate virus replication but can have restrictive polymorphic variants. These analyses, present a limited picture of this host-pathogen co-evolutionary history as they have largely focused on the host partner in these conflicts
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