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

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.

piRNAs derived from ancient viral processed pseudogenes as transgenerational sequence-specific immune memory in mammals

“…Understanding how these gene transfers influence the immunologic distinction between host "self " and viral "nonself " is of practical importance. Interestingly, several host genes derived from retroviruses limit infection by related viruses (Ikeda and Odaka 1983;Hainaut et al 1990;Mura et al 2004;Aswad and Katzourakis 2012;Fujino et al 2014;Yap et al 2014), demonstrating that lateral gene flow from viruses to their vertebrate hosts can mediate transgenerational immune memory; all known examples are mediated by production of dominant negative proteins. RNA-mediated transgenerational antiviral immunity, while common via the CRISPR/Cas system in prokaryotes (Sorek et al 2008), has thus far been reported in only one metazoan, Caenorhabditis elegans (Rechavi et al 2011).…”

Activation of the innate immune response by endogenous retroviruses

“…Also in mice, the capsid-binding restriction factor Fv1 was found to be derived from the gag gene of an ERV (Best et al, 1996). Fv1 protects against infection by a number of exogenous retroviruses by interacting with the capsid and blocking viral DNA entry into the nucleus (Yap et al, 2014). Thus, these restriction factors provide endogenous viral-element-derived immunity by protecting the cell from exogenous retrovirus infection.…”

Antiretroviral restriction factors in mice

“…Interestingly, the Fv1 alleles isolated from mouse species other than Mus musculus show remarkable diversity in the “target” viruses that they restrict (see below) (Yap et al, 2014)…”

“…This presumably reflects ongoing evolutionary battles between viruses and their hosts (Meyerson and Sawyer, 2011); these battles evidently began well before the appearance of contemporary MLVs (Qi et al, 1998; Yan et al, 2009). Indeed, Fv1 loci isolated from different mice can restrict a wide spectrum of retroviruses, including the lentivirus equine infectious anemia virus and the spumaretrovirus feline foamy virus (Yap et al, 2014). It is striking that several of the residues showing evidence of positive selection have previously been identified as critical for restriction of MLVs (Yan et al, 2009).…”

“…The MHR in Fv1 is also critical for Fv1 restriction and contains residues that have experienced positive selection during evolution (Bishop et al, 2001; Yan et al, 2009). The C-terminal portion of Fv1 contains several regions that differ in sequence in different mouse species; this region is known to be important in the specific recognition of MLV p30 CA (Sanz-Ramos and Stoye, 2013; Yap et al, 2014). Interestingly, this overall arrangement of the protein is analogous to that in Trim5α, a restriction factor in primates and other mammals with no sequence similarity to Fv1.…”