A single nucleotide polymorphism in tetherin promotes retrovirus restriction in vivo

PLoS Pathog. 2012;8(3):e1002596. doi: 10.1371/journal.ppat.1002596. Epub 2012 Mar 22.

Abstract

Tetherin is a membrane protein of unusual topology expressed from rodents to humans that accumulates enveloped virus particles on the surface of infected cells. However, whether this 'tethering' activity promotes or restricts retroviral spread during acute retrovirus infection in vivo is controversial. We report here the identification of a single nucleotide polymorphism in the Tetherin gene of NZW/LacJ (NZW) mice that mutated the canonical ATG start site to GTG. Translation of NZW Tetherin from downstream ATGs deleted a conserved dual-tyrosine endosomal sorting motif, resulting in higher cell surface expression and more potent inhibition of Friend retrovirus release compared to C57BL/6 (B6) Tetherin in vitro. Analysis of (B6×NZW)F(1) hybrid mice revealed that increased Tetherin cell surface expression in NZW mice is a recessive trait in vivo. Using a classical genetic backcrossing approach, NZW Tetherin expression strongly correlated with decreased Friend retrovirus replication and pathogenesis. However, the protective effect of NZW Tetherin was not observed in the context of B6 Apobec3/Rfv3 resistance. These findings identify the first functional Tetherin polymorphism within a mammalian host, demonstrate that Tetherin cell surface expression is a key parameter for retroviral restriction, and suggest the existence of a restriction factor hierarchy to counteract pathogenic retrovirus infections in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism
  • Cells, Cultured
  • Disease Models, Animal
  • Endogenous Retroviruses / immunology*
  • Inbreeding
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred Strains
  • Polymorphism, Single Nucleotide*
  • Retroviridae Infections / immunology*
  • Retroviridae Infections / metabolism
  • Retroviridae Infections / virology
  • Viral Load
  • Virus Replication

Substances

  • Antigens, CD
  • BST2 protein, mouse
  • Membrane Glycoproteins