Epstein-Barr virus-driven B cell lymphoma mediated by a unique LMP1-TRAF6 complex

The latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) drives viral B cell transformation andoncogenesis. LMP1's transforming activity depends on its cytoplasmic C-terminal activation region 2(CTAR2), which induces NF-?B and JNK by engaging TNF receptor-associated factor 6 (TRAF6). Themechanism of TRAF6 interaction with LMP1 and its critical role for LMP1 signaling has remained elusive.Here we demonstrate that TRAF6 interacts directly with a novel viral TRAF6 binding motif within CTAR2.Structural modeling supported by NMR and functional studies provides insight into the moleculararchitecture of the LMP1-TRAF6 complex and reveals substantial differences to CD40-TRAF6 interaction.The direct recruitment of TRAF6 to LMP1 is essential for NF-?B activation and survival of LMP1-driven Bcell lymphoma. Disruption of the LMP1-TRAF6 complex by inhibitory peptides interferes with proliferationof EBV-transformed B cells. We identify LMP1-TRAF6 as critical virus-host interface and validate thisinteraction as novel therapeutic target against EBV

Role of Position 627 of PB2 and the Multibasic Cleavage Site of the Hemagglutinin in the Virulence of H5N1 Avian Influenza Virus in Chickens and Ducks

Highly pathogenic H5N1 avian influenza viruses have caused major disease outbreaks in domestic and free-living birds with transmission to humans resulting in 59% mortality amongst 564 cases. The mutation of the amino acid at position 627 of the viral polymerase basic-2 protein (PB2) from glutamic acid (E) in avian isolates to lysine (K) in human isolates is frequently found, but it is not known if this change affects the fitness and pathogenicity of the virus in birds. We show here that horizontal transmission of A/Vietnam/1203/2004 H5N1 (VN/1203) virus in chickens and ducks was not affected by the change of K to E at PB2-627. All chickens died between 21 to 48 hours post infection (pi), while 70% of the ducks survived infection. Virus replication was detected in chickens within 12 hours pi and reached peak titers in spleen, lung and brain between 18 to 24 hours for both viruses. Viral antigen in chickens was predominantly in the endothelium, while in ducks it was present in multiple cell types, including neurons, myocardium, skeletal muscle and connective tissues. Virus replicated to a high titer in chicken thrombocytes and caused upregulation of TLR3 and several cell adhesion molecules, which may explain the rapid virus dissemination and location of viral antigen in endothelium. Virus replication in ducks reached peak values between 2 and 4 days pi in spleen, lung and brain tissues and in contrast to infection in chickens, thrombocytes were not involved. In addition, infection of chickens with low pathogenic VN/1203 caused neuropathology, with E at position PB2-627 causing significantly higher infection rates than K, indicating that it enhances virulence in chickens