Paradox of Nonpathogenicity and Cytopathic Effects：Characterization of Regulator Tas in Foamy Virus Evolution and De-Ubiquitylation of Tas in Virus Duplication

Abstract

\n Background: Foamy virus, which belong to the Spumaretrovirinae subfamily of Retroviridae, bridge the gap between Orthoretrovirinae and Hepadnaviridae, and display a long co-evolution with their hosts. Like other retroviruses, FVs encode a transactivator, Tas, which governs the levels of viral transcripts initiated through binding to the conserved promoters in 5’ long terminal repeat (LTR) and a unique internal promoter (IP). Unlike the other retrovirus, HIV, foamy viruses induced significant cytopathic effects in vitro, but has no significant disease association at the infection level in vivo. The characterization of regulator Tas in the Paradox of nonpathogenicity and cytopathic effects was still unknown.Results: Foamy virus separated from different hosts could form three groups which paralleled with the worldwide distribution of hosts due to geographical isolation. Although the physicochemical properties of different Tas were mainly in line with each other, the conserved motifs analyses still suggested divergences in protein functions. The proteins identified to interact with Tas of PFV, SFVora and SFVagm displayed that the three kinds of foamy viruses regulated different signal pathways and impacted virus-host immune interaction. Interestingly, predictions of interactional factors based on protein sequence showed USP7, a kind of deubiquitinating enzyme, could binding directly to Tas which led to its ubiquitin-dependent proteasome degradation. And this results also implyed that fomay virus could hijacked cytokine USP7 to stabilize the transcriptional activator Tas by de-ubiquitylation and thereby regulate the viral life cycle.Conclusion: Our experiments help to understand the survival strategy of foamy viruses in their hosts.