Research Article: Evolution of the Retroviral Restriction Gene Fv1: Inhibition of Non-MLV Retroviruses

Date Published: March 6, 2014

Publisher: Public Library of Science

Author(s): Melvyn W. Yap, Emily Colbeck, Scott A. Ellis, Jonathan P. Stoye, Jeremy Luban.


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.

Partial Text

Viruses co-evolve with their hosts, upon which they are completely dependent for replication. As the host acquires strategies to restrict virus infection the invaders develop counter measures to evade restriction. The ensuing genetic conflict can play out over an extensive timeframe [1], [2], [3], [4]. Due to the unique replication strategy employed by retroviruses where integration of viral genetic information into the host genome occurs [5], the conflict between virus and host can take an interesting twist. When integration occurs in germ or embryonic cells, the virus can become an endogenous retrovirus (ERV) and inherited through the germ line [6], [7]. As a result, viral gene products can be conscripted to serve as defensive forces against further viral infection [8]. The murine retrovirus restriction gene, Fv1, provides perhaps the prototypic example of one such gene [9].

In this study of Fv1 evolution we have demonstrated that Fv1 shows substantial sequence variation in its C-terminal half, the region of the protein thought to contain determinants of restriction specificity. In addition we have shown that Fv1 is capable of restricting viruses other than its previously defined targets and identified the sequence variation responsible for these novel targets. We note that some Fv1 alleles do not appear to possess an associated restriction activity; it would be of considerable interest to determine whether they recognize other targets.




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