title: Escape variants of the XPR1 gammaretrovirus receptor are rare due to reliance on a splice donor site and a short hypervariable loop.
abstract: Entry determinants in the XPR1 receptor for the xenotropic/polytropic mouse leukemia viruses (XP-MLVs) lie in its third and fourth putative extracellular loops (ECLs). The critical ECL3 receptor determinant overlies a splice donor and is evolutionarily conserved in vertebrate XPR1 genes; 2 of the 3 rare replacement mutations at this site destroy this receptor determinant. The 13 residue ECL4 is hypervariable, and replacement mutations carrying an intact ECL3 site alter but do not abolish receptor activity, including replacement of the entire loop with that of a jellyfish (Cnidaria) XPR1. Because ECL4 deletions are found in all X-MLV-infected Mus subspecies, we deleted each ECL4 residue to determine if deletion-associated restriction is residue-specific or is effected by loop size. All deletions influence receptor function, although different deletions affect different XP-MLVs. Thus, receptor usage of a constrained splice site and a loop that tolerates mutations severely limits the likelihood of host escape mutations.
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, United States.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lu
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, United States.
authors.forename: Carrie
authors.initials: C
authors.lastname: Martin
authors.affiliation: Whitney Laboratory for Marine Bioscience, University of Florida, St. Augustine, FL 32136, United States.
authors.forename: Christelle
authors.initials: C
authors.lastname: Bouchard
authors.affiliation: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, United States. Electronic address: ckozak@niaid.nih.gov.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Kozak
mesh_terms: D000818:Animals; D002460:Cell Line; D003001:Cloning, Molecular; D006224:Cricetinae; D017988:Gammaretrovirus / Q000502:physiology*; D014644:Genetic Variation; D051379:Mice; D022821:RNA Splice Sites; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D037401:Scyphozoa; D053586:Virus Internalization; D000089842:Xenotropic and Polytropic Retrovirus Receptor
chemical_list: D022821:RNA Splice Sites; D043562:Receptors, G-Protein-Coupled; D011991:Receptors, Virus; D000089842:Xenotropic and Polytropic Retrovirus Receptor; C000715268:Xpr1 protein, mouse
keywords: Retrovirus entry; Retrovirus evolution; Retrovirus restriction genes; XPR1 gammaretrovirus receptor; Xenotropic/polytropic gammaretroviruses