DESCRIPTION (provided by applicant): Successful viral replication requires not only the efficient production and spread of progeny, but also evasion of host defense mechanisms that limit replication by killing infected cells. Almost all viruses have developed mechanisms to evade host defense, such as interferon (IFN) activation and/or apoptosis induction. Like most viruses, upon infection of cells, measles virus (MV) is subjected to a variety of intracellular antiviral responses. A better understanding of how measles virus evades the host defense mechanisms will facilitate the design of a more attenuated vaccine strain for use in immunosuppressed patients or for the development of new oncolytic viruses for potential cancer therapy. In recent years, it has become clear that protein products from the P gene of viruses within the Paramyxovirus family specifically reduce the effectiveness of the intracellular antiviral responses. The MV P gene encodes for three proteins, the phosphoprotein P, and two accessory proteins V and C. All three proteins have been implicated in innate immune control, but their mechanisms of action still remains unclear. The research proposed here will further characterize the functions of the P gene products in the control of the antiviral response induced by MV. Our study will be conducted using a dual approach that includes a study of the function of the proteins expressed alone as well as in the context of a viral infection. Toward this goal, we have produced expression plasmids encoding for the individual proteins P/V and recombinant viruses deficient in one or both of the V and C proteins and we will characterize their abilities to evade host defense mechanisms. In aim 1, we will characterize the role of a recently identified tyrosine-rich domain in the common region of the P/V protein and assess its importance in the inhibition of IFN signaling. To understand the molecular mechanism of action of this domain, different steps of the IFN signaling pathway will be analyzed and an identification of cellular partners interacting with this domain will be attempted. In aim 2, we will investigate a potential new function for the V and C proteins that consists to protect the cell against induction of apoptosis. We will characterize the apoptotic pathways activated in infected cells in the absence of the V and C proteins. And in a parallel approach we will investigate the protective properties of the V and C proteins against external inducers of apoptosis. The proposed studies are of an important area to understand how measles virus escapes from innate immunity. The proposed research has relevance to public health, as a better understanding of how measles virus evade host defense will facilitate the design of more attenuated vaccine strain for use in immunosuppressed patients or the development of new oncolytic viruses for cancer therapy.
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