The evolutionary interplay between exogenous and endogenous sheep betaretroviruses

QR355 Virology

Armezzani, Alessia ; Palmarini, Massimo

University:University of Glasgow

Department:School of Veterinary Medicine

关键词: retroviruses, endogenous retroviruses, JSRV, enJSRV, signal peptide, evolutionary interplay between host and pathogen;   

Others  :  http://theses.gla.ac.uk/3265/1/2012armezzaniphd.pdf

来源: University of Glasgow

【 摘 要 】

Retroviruses must integrate their genome into the host DNA as a necessary step of their replication cycle. Normally, retroviruses integrate into somatic cells and are transmitted, from infected to uninfected hosts, as “exogenous” retroviruses. On rare occasions, they can infect germ line cells and become part of the host genome as “endogenous” retroviruses (ERVs), which are transmitted vertically to the offspring and inherited as Mendelian genes. During evolution, most ERVs have accumulated mutations that rendered them defective and unable to produce infectious viral particles. Some ERVs, however, have maintained intact open reading frames for some of their genes, and have been co-opted by the host as they fulfil important biological functions. Sheep betaretroviruses represent a unique 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) co-exists with the highly related endogenous JSRVs (enJSRVs). The sheep genome harbours at least twenty-seven enJSRV loci and, most likely, the process of endogenization is still occurring.During evolution, one of these enJSRV loci, enJS56A1, has acquired a defectiveand transdominant Gag polyprotein that blocks the late replication steps ofrelated retroviruses, by a mechanism known as JSRV late restriction (JLR).Interestingly, enJSRV-26, a provirus that integrated in the sheep germ line lessthan two hundred years ago, possesses the unique ability to escape JLR. In thisthesis, the molecular basis of JLR escape was investigated. The maindeterminant of JLR escape was identified in the signal peptide of enJSRV-26envelope protein (SP26). A single amino acid substitution in SP26 was found tobe responsible for altering its intracellular localization as well as its function asa post-transcriptional regulator of viral gene expression. Interestingly,interference assays demonstrated that enJSRV-26 relies on the presence of thefunctional signal peptide of enJS56A1 envelope protein (SP56) in order to escapeJLR. In addition, the ratio between enJSRV-26 and enJS56A1 Gag polyproteinswas found to be critical to elude JLR. Finally, sequence analyses revealed thatthe domestic sheep has acquired, by genome amplification, several copies of theenJS56A1 provirus, reinforcing the hypothesis that this locus has provided anevolutionary advantage to the host. This study unveils critical aspects of JLRthat were previously unknown, and provides new insights on the molecular mechanisms governing the interplay between endogenous and exogenous sheepbetaretroviruses.