Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Mar 6;10(3):e1003968.
doi: 10.1371/journal.ppat.1003968. eCollection 2014 Mar.

Evolution of the retroviral restriction gene Fv1: inhibition of non-MLV retroviruses

Melvyn W Yap  1 , Emily Colbeck  1 , Scott A Ellis  1 , Jonathan P Stoye  2
Affiliations

Evolution of the retroviral restriction gene Fv1: inhibition of non-MLV retroviruses

Melvyn W Yap et al. PLoS Pathog. .

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Features of Fv1.
At the top of the figure is a schematic of the Fv1 protein showing the relative positions of the previously mapped functional domains including coiled coil and major homology regions as well as the host range specificity regions previously defined by a comparison of Fv1n and Fv1b . Below is shown the positions of four variable regions (VA–D), the amino acid differences that define them and the number of times each amino acid occurs. Based on a comparison of 19 mice (Table 1 plus Table 2).
Figure 2
Figure 2. The C-terminal region of selected Fv1 proteins.
Nucleic acid and predicted amino acids found at the C-terminus of selected Fv1 genes. The twelve nucleotides shown in purple for Fv1n are found 1.3 kb downstream in Fv1b . Sequences shown in blue (FAM, MIN) correspond to nucleotides 1–27 of the consensus B1 repeat . The sequences in red (PTX) might also come from a rearranged B1 repeat as they correspond to nucleotides 30–44 and 56–65 of the consensus sequence. The nucleotide in orange corresponds to a unique point mutation found in Mus m. spretus resulting in a novel stop codon.
Figure 3
Figure 3. Phylogenetic tree of Fv1 sequences.
The tree was generated from the open reading frames listed in Tables 1 and 2 (bases 1 to 1278 in Fv1b) using the MegAlign programme from the DNASTAR Lasergene package. The highly divergent C-terminus was excluded from the analysis and the aspartic acid residue at position 426 (Fv1b numbering), which was the last residue conserved in all the sequences, was chosen as the cut-off point. The number of substitution events is shown at the bottom of the tree while the distances between sequence pairs is represented by the length of the branch pairs. The distance values were calculated using the Kimura distance formula that takes into account the number of non-gap mismatches and silent substitutions.
Figure 4
Figure 4. Staging restriction blocks in novel Fv1s.
MDTF cells were transduced with Fv1CAR1 and Fv1SPR1, then stable Fv1-expressing cell lines selected and tested for restriction of virus replication by FACS (A, B) or by PCR to measure viral DNA synthesis or formation of circular viral DNA containing two LTRs (C, D).
Figure 5
Figure 5. Mapping the determinants of FFV restriction by Fv1 from M. m. caroli.
(A) Analysis of restriction by chimeric Fv1 constructs. (B) Analysis of restriction by site directed mutant forms of Fv1.
Figure 6
Figure 6. Mapping the determinants of EIAV restriction by Fv1 from M. m. spretus.
(A) Analysis of restriction by chimeric Fv1 constructs. (B) Analysis of restriction by site directed mutant forms of Fv1.
Figure 7
Figure 7. Properties of the variable regions of Fv1.
Proteins corresponding to the Fv1SPR1, Fv1CAR1 and Fv1nr alleles are illustrated. Shaded positions indicate amino acids showing positive selection , residues in triangles have been implicated in restriction specificity (this paper, [16], [48]).
Figure 8
Figure 8. Events in the evolution of the Fv1 gene.
A phylogenetic tree showing the approximate times of Fv1 acquisition and hypothetical virus infections leading to selection of new retroviral restriction activities. Colored mice indicate Fv1 activity against at least one virus.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Compton AA, Hirsch VM, Emerman M (2012) The host restriction factor APOBEC3G and retroviral Vif protein coeveolve due to ongoing genetic conflict. Cell Host and Microbe 11: 91–98. - PMC - PubMed
    1. Emerman M, Malik HS (2010) Paleovirology–modern consequences of ancient viruses. PLoS Biol 8: e1000301. - PMC - PubMed
    1. Meyerson NR, Sawyer SL (2011) Two-stepping through time: mammals and viruses. Trends Microbiol 19: 286–294. - PMC - PubMed
    1. Sauter D, Unterweger D, Vogl M, Usmani SM, Heigele A, et al. (2012) Human tetherin exerts strong selection pressure on the HIV-1 group N Vpu protein. PLoS Pathog 8: e1003093. - PMC - PubMed
    1. Goff SP (2007) Retroviridae: The retroviruses and their replication. In: Knipe DM, Griffin DE, Lamb RA, Strauss SE, Howley, Marting MA, Roizman B, editors. Fields Virology. Philadelphia: Lippincott Williams & Wilkins. Chapter 55: : pp1999–2069.

Publication types

LinkOut - more resources