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Title: Late restriction induced by an endogenous retrovirus
Author: Murcia, Pablo Ramiro
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2007
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Exogenous retroviruses (i.e. horizontally transmitted) must integrate their proviral DNA into the host's genome as part of the retroviral cycle. Therefore, infections of the germ line can give rise to vertically transmitted endogenous retroviruses (ERVs). ERVs are present in all vertebrates. During evolution, most ERVs have accumulated mutations and/or deletions that hampered their ability to replicate and hence to harm the host. However, some ERVs have retained at least some of their open reading frames intact even after several million years. One possible reason for the selection of ERVs is that they protected the host against incoming pathogenic exogenous retroviruses. The fact that the vast majority of ERVs do not possess circulating exogenous counterparts supports this view. Ovine pulmonary adenocarcinoma (OPA) is a transmissible lung cancer of sheep caused by a Betaretrovirus known as Jaagsiekte sheep retrovirus (JSRV). Notably, the sheep genome possesses approximately 30 ERVs highly related to JSRV (and hence referred to as enJSRVs). A specific enJSRV provirus, termed enJS56Al, acts as a transdominant restriction factor that blocks the exogenous JSRV at late stages of the replication cycle. The main determinant of this block (termed JLR for JSRV late restriction) has been mapped to the N-terminal region of the Gag polyprotein, more precisely to residue 21 of the matrix protein, hi this study, the molecular basis of JLR was investigated by functionally characterizing the JSRV and enJS56Al Gag polyproteins. Putative Gag trafficking signals, such as membrane binding (M) and late domains (L) were identified, although it was determined that these domains lack any involvement in JLR. enJS56Al- expression constructs bearing truncated Gags were unable to block JSRV, indicating that an intact Gag polyprotein is required for JLR. Moreover, intracellular colocalization and protein-protein interaction between JSRV and enJS56Al Gag molecules was determined by confocal microscopy and co-immunoprecipitation, respectively. Complementation assays suggest that JSRV and enJS56Al Gag likely co-assemble. These data are supported by the fact that deletion of the major homology region of enJS56Al Gag allows JSRV to escape JLR. Confocal microscopy experiments indicate that JSRV must reach the pericentriolar region as part of its normal cell cycle and that JLR takes place before this stage. This work unveils basic aspects of JSRV biology that were previously unknown. It also provides insight on the molecular basis of JLR, highlighting the dynamic evolutionary interplay between viruses and host.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral