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Title: Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses


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Chatterjee, Srirupa, Luthra, Priya, Esaulova, Ekaterina, Agapov, Eugene, Yen, Benjamin C., Borek, Dominika M., Edwards, Megan R., Mittal, Anuradha, Jordan, David S., Ramanan, Parameshwar, Moore, Martin L., Pappu, Rohit V., Holtzman, Michael J., Artyomov, Maxim N., Basler, Christopher F., Amarasinghe, Gaya K., and Leung, Daisy W.. Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses. United States: N. p., 2017. Web. doi:10.1038/nmicrobiol.2017.101.
Chatterjee, Srirupa, Luthra, Priya, Esaulova, Ekaterina, Agapov, Eugene, Yen, Benjamin C., Borek, Dominika M., Edwards, Megan R., Mittal, Anuradha, Jordan, David S., Ramanan, Parameshwar, Moore, Martin L., Pappu, Rohit V., Holtzman, Michael J., Artyomov, Maxim N., Basler, Christopher F., Amarasinghe, Gaya K., & Leung, Daisy W.. Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses. United States. doi:10.1038/nmicrobiol.2017.101.
Chatterjee, Srirupa, Luthra, Priya, Esaulova, Ekaterina, Agapov, Eugene, Yen, Benjamin C., Borek, Dominika M., Edwards, Megan R., Mittal, Anuradha, Jordan, David S., Ramanan, Parameshwar, Moore, Martin L., Pappu, Rohit V., Holtzman, Michael J., Artyomov, Maxim N., Basler, Christopher F., Amarasinghe, Gaya K., and Leung, Daisy W.. Fri . "Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses". United States. doi:10.1038/nmicrobiol.2017.101.
@article{osti_1374614,
title = {Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses},
author = {Chatterjee, Srirupa and Luthra, Priya and Esaulova, Ekaterina and Agapov, Eugene and Yen, Benjamin C. and Borek, Dominika M. and Edwards, Megan R. and Mittal, Anuradha and Jordan, David S. and Ramanan, Parameshwar and Moore, Martin L. and Pappu, Rohit V. and Holtzman, Michael J. and Artyomov, Maxim N. and Basler, Christopher F. and Amarasinghe, Gaya K. and Leung, Daisy W.},
abstractNote = {},
doi = {10.1038/nmicrobiol.2017.101},
journal = {Nature Microbiology},
number = 06, 2017,
volume = 2,
place = {United States},
year = {Fri Jun 30 00:00:00 EDT 2017},
month = {Fri Jun 30 00:00:00 EDT 2017}
}
  • Paramyxoviruses have been shown to produce proteins that inhibit interferon production and signaling. For human respiratory syncytial virus (RSV), the nonstructural NS1 and NS2 proteins have been shown to have interferon antagonist activity through an unknown mechanism. To understand further the functions of NS1 and NS2, we generated recombinant RSV in which both NS1 and NS2 were replaced by the PIV5 V protein, which has well-characterized IFN antagonist activities ({delta}NS1/2-V). Expression of V was able to partially inhibit IFN responses in {delta}NS1/2-V-infected cells. In addition, the replication kinetics of {delta}NS1/2-V were intermediate between {delta}NS1/2 and wild-type (rA2) in A549 cells.more » However, expression of V did not affect the ability of {delta}NS1/2-V to activate IRF3 nuclear translocation and IFN{beta} transcription. These data indicate that V was able to replace some of the IFN inhibitory functions of the RSV NS1 and NS2 proteins, but also that NS1 and NS2 have functions in viral replication beyond IFN antagonism.« less
  • Motavizumab is {approx}tenfold more potent than its predecessor, palivizumab (Synagis), the FDA-approved monoclonal antibody used to prevent respiratory syncytial virus (RSV) infection. The structure of motavizumab in complex with a 24-residue peptide corresponding to its epitope on the RSV fusion (F) glycoprotein reveals the structural basis for this greater potency. Modeling suggests that motavizumab recognizes a different quaternary configuration of the F glycoprotein than that observed in a homologous structure.
  • Respiratory syncytial virus (RSV), the main cause of infant bronchiolitis, remains a major unmet vaccine need despite more than 40 years of vaccine research. Vaccine candidates based on a chief RSV neutralization antigen, the fusion (F) glycoprotein, have foundered due to problems with stability, purity, reproducibility, and potency. Crystal structures of related parainfluenza F glycoproteins have revealed a large conformational change between the prefusion and postfusion states, suggesting that postfusion F antigens might not efficiently elicit neutralizing antibodies. We have generated a homogeneous, stable, and reproducible postfusion RSV F immunogen that elicits high titers of neutralizing antibodies in immunized animals.more » The 3.2-{angstrom} X-ray crystal structure of this substantially complete RSV F reveals important differences from homology-based structural models. Specifically, the RSV F crystal structure demonstrates the exposure of key neutralizing antibody binding sites on the surface of the postfusion RSV F trimer. This unanticipated structural feature explains the engineered RSV F antigen's efficiency as an immunogen. This work illustrates how structural-based antigen design can guide the rational optimization of candidate vaccine antigens.« less