Fv1 is the prototypic restriction factor that protects against infection by the murine leukemia virus (MLV). It was first identified in cells that were derived from laboratory mice and was found to be homologous to the gag gene of an endogenous retrovirus (ERV). To understand the evolution of the host restriction gene from its retroviral origins, Fv1s from wild mice were isolated and characterized. Most of these possess intact open reading frames but not all restricted N-, B-, NR-or NB-tropic MLVs, suggesting that other viruses could have played a role in the selection of the gene. The Fv1s from Mus spretus and Mus caroli were found to restrict equine infectious anemia virus (EIAV) and feline foamy virus (FFV) respectively, indicating that Fv1 could have a broader target range than previously thought, including activity against lentiviruses and spumaviruses. Analyses of the Fv1 sequences revealed a number of residues in the C-terminal region that had evolved under positive selection. Four of these selected residues were found to be involved in the novel restriction by mapping studies. These results strengthen the similarities between the two capsid binding restriction factors, Fv1 and TRIM5α, which support the hypothesis that Fv1 defended mice against waves of retroviral infection possibly including non-MLVs as well as MLVs.
We have followed the evolution of the retroviral restriction gene, Fv1, by functional analysis. We show that Fv1 can recognize and restrict a wider range of retroviruses than previously thought including examples from the gammaretrovirus, lentivirus and foamy virus genera. Nearly every Fv1 tested showed a different pattern of restriction activity. We also identify several hypervariable regions in the coding sequence containing positively selected amino acids that we show to be directly involved in determining restriction specificity. Our results strengthen the analogy between Fv1 and another capsid-binding, retrovirus restriction factor, TRIM5α. Although they share no sequence identity they appear to share a similar design and appear likely to recognise different targets by a mechanism involving multiple weak interactions between a virus-binding domain containing several variable regions and the surface of the viral capsid. We also describe a pattern of constant genetic change, implying that different species of Mus have evolved in the face of ever-changing retroviral threats by viruses of different kinds.