Evolution of functional and sequence variants of the mammalian XPR1 receptor for mouse xenotropic gammaretroviruses and the human-derived retrovirus XMRV. — CFSMEATLAS
E3 PreliminaryPreliminaryPEM not requiredMechanisticPeer-reviewedMachine draft
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Evolution of functional and sequence variants of the mammalian XPR1 receptor for mouse xenotropic gammaretroviruses and the human-derived retrovirus XMRV.
Yan, Yuhe, Liu, Qingping, Wollenberg, Kurt et al. · Journal of virology · 2010 · DOI
Quick Summary
This study examined how a protein called XPR1 on cell surfaces acts as a doorway for certain viruses, including XMRV (a virus found in some people with chronic fatigue syndrome). Researchers looked at how this protein varies across different mouse species and other mammals to understand why some animals can be infected by these viruses and others cannot. They identified genetic changes in the XPR1 protein that determine whether cells allow viruses to enter.
Why It Matters
Understanding how XMRV interacts with human cell receptors is crucial for ME/CFS research, as XMRV has been detected in some patient populations. This mechanistic work on viral entry pathways could help explain infection susceptibility and inform therapeutic strategies targeting viral entry. Clarifying the specific receptor requirements of XMRV may also help resolve inconsistencies in XMRV detection and association studies.
Observed Findings
Five distinct Xpr1 gene variants exist in Mus species, including a novel fifth variant in M. molossinus and M. musculus.
Rodent Xpr1 genes show evidence of positive selection with multiple codons under evolutionary constraint.
Two specific amino acid residues (I579 and T583) in the fourth extracellular loop were identified as functionally important for virus entry.
Hamster and gerbil cells restrict XMRV infection, indicating unique receptor requirements for XMRV distinct from other X/P-MLVs.
Wild mice do not carry the X-MLV-restrictive laboratory mouse Xpr1 allele despite extensive screening.
Inferred Conclusions
Host-pathogen coevolution has shaped Xpr1 genetic diversity across mammalian species through positive selection and functional constraint.
XMRV has distinct receptor requirements compared to other mouse leukemia viruses, suggesting specialized evolutionary adaptation.
Specific residues in the XPR1 receptor's fourth extracellular domain are critical determinants of gammaretrovirus entry efficiency and species tropism.
Remaining Questions
Why does the X-MLV-restrictive allele found in laboratory mice not appear in wild mouse populations, and what selective pressures maintain variation in natural settings?
What This Study Does Not Prove
This study does not prove that XMRV causes ME/CFS or that it is present in ME/CFS patients—it only characterizes how the virus uses the XPR1 receptor to enter cells. The work is conducted primarily in rodent and cell culture systems and does not directly demonstrate XMRV prevalence or pathogenic mechanisms in humans. Mechanistic receptor studies cannot establish causation of disease or definitively explain clinical associations.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →