"Ménage à Trois": the evolutionary interplay between JSRV, enJSRVs and domestic sheep

Abstract

Sheep betaretroviruses represent a fascinating model to study the complex evolutionary interplay between host and pathogen in natural settings. In infected sheep, the exogenous and pathogenic Jaagsiekte sheep retrovirus (JSRV) coexists with a variety of highly related endogenous JSRVs, referred to as enJSRVs. During evolution, some of them were co-opted by the host as they fulfilled important biological functions, including placental development and protection against related exogenous retroviruses. In particular, two enJSRV loci, enJS56A1 and enJSRV-20, were positively selected during sheep domestication due to their ability to interfere with the replication of related competent retroviruses. Interestingly, viruses escaping these transdominant enJSRVs have recently emerged, probably less than 200 years ago. Overall, these findings suggest that in sheep the process of endogenization is still ongoing and, therefore, the evolutionary interplay between endogenous and exogenous sheep betaretroviruses and their host has not yet reached an equilibrium.

Figure 1

JSRV genomic organization. The JSRV genome encodes gag, pro, pol and env genes and orf-x, an additional open reading frame of unknown function (top). On the bottom are indicated the polyprotein precursors derived from each gene that are cleaved by the cellular machinery. See text for more details. LTR, long terminal repeat; MA, matrix; p15, 15 kDa protein; L domain, late domain; CA, capsid; NC, nucleocapsid; p4, 4 kDa protein; PR, protease; dUTPase, deoxyuridine triphosphatase; RT, reverse transcriptase; IN, integrase; SU, surface domain; TM, transmembrane domain; YXXM, Y indicates a tyrosine residue, X any amino acid and M a methionine residue (according to the single-letter code).

Figure 2

Genetic organization of enJSRV proviruses. All the genomic sequences flanking enJSRV proviruses display a six base pair duplication that is the hallmark of retroviral integration. The only exceptions are enJSRV-20, which contains a portion of an env gene before the 5' LTR (indicated by a dark grey box and ? mark), and enJSRV-2 that does not possess the same six base pairs sequences flanking its LTRs. At the top are shown the five enJSRVs displaying an intact genomic organization, typical of replication competent exogenous retroviruses. The two transdominant proviruses enJS56A1 and enJSRV-20 possess a tryptophan residue (W) at position 21 of Gag and identical 3' genomic flanking regions. The enJSRV-6 locus contains an additional methionine (M) in Env besides the canonical start codon present in JSRV and other enJSRV loci. In addition, in enJSRV-6, gag and pro are oriented in opposite direction compared to the 5' LTR, 3' LTR and env (indicated by horizontal arrows). enJSRV-1 possesses a long interspersed nucleotide element (LINE) within the pol coding region. Note that the following enJSRVs are insertionally polymorphic in the genome of domestic sheep: enJSRV-7, enJSRV-8, enJSRV-15, enJSRV-16, enJSRV-18, enJSRV-26 and enJS5F16. Premature termination codons are represented by a vertical line and an asterisk (*). Large deletions in proviral genomes are indicated by hatched boxes. enJSRV, endogenous Jaagsiekte sheep retrovirus; LTR, long terminal repeat (Figure modified from Arnaud et al. 2007 PLoS Pathogens) [6].

Figure 3

Hypothetical adaptation and counter-adaptation events between enJSRVs, JSRV and their host during evolution. See text for more details. enJSRV, endogenous Jaagsiekte sheep retrovirus; JLR, JSRV late restriction; JSRV, Jaagsiekte sheep retrovirus; oBST-2, ovine bone marrow stromal cell antigen 2; R21, arginine residue at position 21 of enJS56A1/enJSRV-20 Gag; W21, tryptophan residue at position 21 of enJS56A1/enJSRV-20 Gag (Figure modified from Varela et al. 2009) [65].

Figure 4

Mechanisms of restriction induced by enJSRVs, and JLR escape. enJSRVs can inhibit JSRV entry at the cell entry by receptor interference, as both endogenous and exogenous retroviruses use Hyal2 as cellular receptor. The binding between enJSRVs Env and Hyal2 (either at the plasma membrane or in the cytoplasm) decreases the availability of the latter at the cell surface, thereby inhibiting JSRV entry into target cells (1); In addition, some enJSRVs, such as enJS56A1, can block JSRV at post-integration steps of viral cycle. This mechanism of interference, known as JLR, most likely impairs viral particle transport or exit, and is exerted by transdominant Gag proteins: these form aggregates with JSRV Gag that are subsequently targeted to the proteasome where they are degraded (2); The ability of enJSRV-26 to elude JLR restriction is dependent on the impaired function of its SP. Consequently, the enJSRV-26 and enJS56A1 unspliced RNAs compete for the only functional SP (i.e., SP56), resulting in a reduced expression of transdominant Gag. Thus an unbalanced ratio between enJSRV-26 and enJS56A1 Gag polyproteins is established leading, at the same time, to a partial degradation and particle release of the first (3). enJSRV endogenous Jaagsiekte sheep retrovirus; Hyal2 hyaluronidase2; JSRV Jaagsiekte sheep retrovirus.