5 years ago

Mutation of the Putative Immunosuppressive Domain of the Retroviral Envelope Glycoprotein Compromises Infectivity.

Kassiotis G, Stoye JP, Jenkins B, Mothes W, Merkenschlager J, Eksmond U
The envelope glycoprotein of diverse endogenous and exogenous retroviruses is considered inherently immunosuppressive. Extensive work mapped the immunosuppressive activity to a highly conserved domain, termed the immunosuppressive domain (ISD), in the transmembrane (TM) subunit of the envelope glycoprotein and identified two naturally polymorphic key residues that afford immunosuppressive activity to distinct envelope glycoproteins. Concurrent mutation of these two key residues (E14R and A20F) in the envelope glycoprotein of Friend murine leukemia virus (F-MLV) ISD has been reported to abolish its immunosuppressive activity, without affecting its fusogenicity, and to weaken the ability of the virus to replicate specifically in immunocompetent hosts. Here, we show that mutation of these key residues did in fact result in substantial loss of F-MLV infectivity, independent of host immunity, challenging associations between the two. Notably, loss of infectivity incurred by the E14R and A20F double ISD mutant F-MLV was conditional on expression of the ecotropic envelope receptor mCAT1 (cationic amino acid transporter -1) in the virus-producing cell. Indeed the mutant F-MLV retained infectivity when produced by human cells, naturally lacking mCAT1 expression, but not by murine cells. Furthermore, mCAT1 overexpression in human cells impaired the infectivity of both double mutant and wild-type F-MLV, suggesting a finely-tuned relationship between levels of mCAT1 in the producer cell and infectivity of the virions produced. An adverse effect on this relationship, rather than disruption of the putative ISD, is therefore more likely to explain the loss of F-MLV infectivity incurred by mutations in the key E14 and A20 ISD residues.IMPORTANCE Retroviruses can interact with their hosts in ways that, although not entirely understood, can greatly influence their pathogenic potential. One such example is a putative immunosuppressive activity, mapped to a conserved domain of the retroviral envelope glycoprotein of several exogenous, as well as endogenous retroviruses. In this study, mutations naturally found in some envelope glycoproteins lacking immunosuppressive activity were shown to affect retrovirus infectivity, only if the host cell that produces the retrovirus also expresses the cellular entry receptor. These findings shed light on a novel role for this conserved domain in providing the necessary stability to the envelope glycoprotein, in order to withstand interaction with the cellular receptor during virus formation. This function of the domain is critical for further elucidation of the mechanism of immunosuppression mediated by the retroviral envelope glycoprotein.

Publisher URL: https://www.ncbi.nlm.nih.gov/pubmed/28814524

DOI: PubMed:28814524

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