Full Title: Evolution of functional and sequence variants of the mammalian XPR1 receptor for mouse xenotropic gammaretroviruses and the human-derived XMRV.
Authors: Yan Y, Liu Q, Wollenberg K, Martin C, Buckler-White A, Kozak CA.
Publication: Journal of Virology
Publication Date: 15th September 2010
Laboratory of Molecular Microbiology, Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
Genetic conflicts between retroviruses and their receptors result in the evolution of novel host entry restrictions and novel virus envelopes, and such variants can influence trans-species transmission. We screened rodents and other mammals for sequence variation in the Xpr1 receptor for the mouse xenotropic/polytropic (X/P-MLV) gammaretrovirus family and for susceptibility to mouse-derived X/P-MLVs and to XMRV, an X-MLV-like virus isolated from humans with prostate cancer and chronic fatigue syndrome. We identified multiple distinct susceptibility phenotypes; these include the 4 known Xpr1 variants in Mus and a novel 5th Xpr1 found in M. molossinus and M. musculus. We describe the geographic and species distribution of the Mus Xpr1 variants, but failed to find the X-MLV-restrictive laboratory mouse allele in any wild mouse. We used mutagenesis and phylogenetic analysis to evaluate the functional contributions made by constrained, variable, and deleted residues. Rodent Xpr1 is under positive selection indicating a history of host-pathogen conflicts; several codons under selection have known roles in virus entry. All non-Mus mammals are susceptible to mouse X-MLVs, but some restrict other members of the X/P-MLV family and the resistance of hamster and gerbil cells to XMRV indicates that XMRV has unique receptor requirements. We show that the hypervariable fourth extracellular XPR1 loop (ECL4) contains 3 evolutionarily constrained residues that do not contribute to receptor function, we identify 2 novel residues important for virus entry (I579, T583), and we describe a unique pattern of ECL4 variation in the 3 virus-restrictive Xpr1 variants found in MLV-infected house mice; these mice carry different deletions in ECL4 suggesting either that these sites or loop size affects receptor function.