A Paradigm for Virus–Host Coevolution: Sequential Counter-Adaptations between Endogenous and Exogenous Retroviruses

Abstract

Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections of the host germline transmitted vertically from generation to generation. It is hypothesized that some ERVs are used by the host as restriction factors to block the infection of pathogenic retroviruses. Indeed, some ERVs efficiently interfere with the replication of related exogenous retroviruses. However, data suggesting that these mechanisms have influenced the coevolution of endogenous and/or exogenous retroviruses and their hosts have been more difficult to obtain. Sheep are an interesting model system to study retrovirus-host coevolution because of the coexistence in this animal species of two exogenous (i.e., horizontally transmitted) oncogenic retroviruses, Jaagsiekte sheep retrovirus and Enzootic nasal tumor virus, with highly related and biologically active endogenous retroviruses (enJSRVs). Here, we isolated and characterized the evolutionary history and molecular virology of 27 enJSRV proviruses. enJSRVs have been integrating in the host genome for the last 5–7 million y. Two enJSRV proviruses (enJS56A1 and enJSRV-20), which entered the host genome within the last 3 million y (before and during speciation within the genus Ovis), acquired in two temporally distinct events a defective Gag polyprotein resulting in a transdominant phenotype able to block late replication steps of related exogenous retroviruses. Both transdominant proviruses became fixed in the host genome before or around sheep domestication (∼ 9,000 y ago). Interestingly, a provirus escaping the transdominant enJSRVs has emerged very recently, most likely within the last 200 y. Thus, we determined sequentially distinct events during evolution that are indicative of an evolutionary antagonism between endogenous and exogenous retroviruses. This study strongly suggests that endogenization and selection of ERVs acting as restriction factors is a mechanism used by the host to fight retroviral infections.

Evolutionary dynamics of endogenous Jaagsiekte sheep retroviruses proliferation in the domestic sheep, mouflon and Pyrenean chamois

“…The analysis included previously published enJSRV sequences from O. aries that are available in GenBank and that overlapped completely the relevant region of enJSRV (GenBank accession numbers: AF136224, AF136225, AF153615 and EF680296-319) (Palmarini et al, 2000;Arnaud et al, 2007). Phylogenetic analyses of the resulting provirus sequences revealed two major clades (Figure 3) previously identified by Palmarini et al (2000) and designed enJSRV-A and enJSRV-B, which cluster ancient and recent insertions, respectively .…”

“…These LTR primers were designed using conserved regions of previously sequenced enJSRV LTRs in sheep (GenBank accession numbers: AF136224, AF136225, AF153615 and EF680296-319) (Palmarini et al, 2000;Arnaud et al, 2007). Primer sequences and locations are shown in Figure 1.…”

“…We followed the nomenclature used by Palmarini et al (2000) and Arnaud et al (2007) for the previously characterized enJSRVs. The two major clades previously identified by Palmarini et al (2000) and designed enJSRV-A and enJSRV-B were used to describe the two main phylogenetic clusters .…”

“…Owing to the short length of the enJSRV copies amplified experimentally in this work, we decided to map them by using whole nucleotide sequences of previously sequenced enJSRVs (GenBank accession numbers: AF136224, AF136225, AF153615 and EF680296-319) (Palmarini et al, 2000;Arnaud et al, 2007). This strategy was based on the similarity of sequences, and previously sequenced enJSRVs were used as a search query.…”

“…Moreover, some newly inserted proviruses acquired a defective Gag polyprotein resulting in a transdominant phenotype able to block late replication steps of related exogenous retroviruses (Mura et al, 2004;Arnaud et al, 2007;Murcia et al, 2007;Armezzani et al, 2011).…”