EXCEED THE SPACE PROVIDED. Apoptosis plays important roles in pathogenesis of paramyxoviruses which includes many important pathogens. Mechanisms of activation and inhibition of apoptotic pathways by paramyxoviruses are not well understood. Tumor necrosis factor alpha (TNF) can be induced by paramyxovirus infection and can cause apoptosis of infected cells. Simian virus 5 (SV5), a paramyxovirus, does not cause apoptosis. However, deletion of the 44- amino-acid-residue small hydrophobic (SH) gene from SV5 resulted in a mutant virus that induced apoptosis and increased expression of TNF. It is hypothesized that the SH protein blocks apoptotic pathways activated by TNF and the SH protein may define a new class of anti-apoptosis proteins. Long term goals of this work are to understand how paramyxoviruses interact with host cell apoptotic pathways. The proposal focuses on following aims: (1) investigate mechanism of inhibition of TNF signaling pathways by the SH protein. It is shown in the preliminary studies that the SH protein is sufficient to inhibit TNF signaling. Key residues of SH that are important for its inhibitory effect and host cells with which SH interacts will be identified; (2) investigate mechanism of increased expression of TNF in the mutant virus infected cells. Expression of TNF in virus infected cells will be examined at transcriptional and translational levels. SV5 protein responsible for activating expression will be identified; (3) study anti-apoptosis functions of SH proteins encoded by other paramyxoviruses. SV5 containing SH genes from other paramyxoviruses in place of the SH gene of SV5 will be generated. Growth characteristics of the hybrid SV5 viruses will be examined and their abilities to induce apoptosis will be analyzed; and (4) investigate inhibition of apoptotic pathways by the hemagglutinin-neuraminidase (HN) protein of SV5. Like SH, HN, a type II membrane protein, has a small cytoplasmic tail of 16 amino acid residues. A recombinant SV5 with a deletion of the tail of HN induced apoptosis in HeLa T4 cells. The involvement of the HN protein in inhibiting apoptosis will be studied. PERFORMANCE SITE ========================================Section End===========================================
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