MRCE Project Abstract

2009

Viral Evasion of IFN Function by Decoy Receptor Sequestration

Daved Fremont, PhD

Interferon mediated signaling is a favored target of viral subterfuge. In this proposal we set out to explore the biophysical and functional attributes of two distinct IFN binding proteins (IFN-bp) that selectively neutralize the biological effects of type-I & III IFNs. Ectromelia virus (EV) encodes a secreted IFN binding protein (IFN-bp) that promiscuously binds and blocks the antiviral effects of type-I IFNs in a species independent manner, with the notable exception of murine IFN-b that it fails to inhibit. The Yaba-like disease virus (YLDV) encodes a related IFN-bp that capably inhibits both primate type-I & III IFNs. Our proposed studies aim to dissect the mechanism and consequences of viral decoy receptor mediated IFN sequestration. We are particularly interested in engineering novel IFN-bp variants with selective loss or gain of function that can be evaluated in mouse infectious disease models.

MRCE Publications

A therapeutic antibody against west nile virus neutralizes infection by blocking fusion within endosomes. Thompson BS, Moesker B, Smit JM, Wilschut J, Diamond MS, Fremont DH. PLoS Pathog: 2009 May;5(5):e1000453.

The structural immunology of antibody protection against West Nile virus. Diamond MS, Pierson TC, Fremont DH. Immunol Rev: 2008 Oct;225(1):212-25.

The structural immunology of antibody protection against West Nile virus. Diamond MS, Pierson TC, Fremont DH. Immunol Rev: 2008 Oct;225:212-25.

Binding of a neutralizing antibody to dengue virus alters the arrangement of surface glycoproteins. Lok SM, Kostyuchenko V, Nybakken GE, Holdaway HA, Battisti AJ, Sukupolvi-Petty S, Sedlak D, Fremont DH, Chipman PR, Roehrig JT, Diamond MS, Kuhn RJ, Rossmann MG. Nat Struct Mol Biol: 2008 Mar;15(3):312-7.

Human major histocompatibility complex (MHC) class I molecules with. Truscott SM, Wang X, Lybarger L, Biddison WE, McBerry C, Martinko
JM, Connolly JM, Linette GP, Fremont DH, Hansen TH, Carreno BM. J Biol Chem: 2008 Mar 21;283(12):7480-90.

Human MHC class I molecules with disulfide traps secure disease-related antigenic peptides and exclude competitor peptides. Steven M Truscott, Xiaoli Wang, Lonnie Lybarger, William E Biddison, Cortez McBerry, John M Martinko, Janet M Connolly, Gerald P Linette, Daved H Fremont, Ted H Hansen and Beatriz M Carreno. Journal of Biological Chemistry: 2008 Mar 21;283(12):7480-90.

Complement protein c1q inhibits antibody-dependent enhancement of flavivirus infection in an IgG subclass-specific manner. Mehlhop E, Ansarah-Sobrinho C, Johnson S, Engle M, Fremont DH, Pierson TC, Diamond MS. Cell Host Microbe: 2007;2(6):417-26.

Type- and Sub-Complex-Specific Neutralizing Antibodies Against Domain III of Dengue Virus Type-2 Envelope Protein Recognize Adjacent Epitopes. Sukupolvi-Petty S, Austin SK, Purtha WE, Oliphant T, Nybakken GE, Schlesinger JJ, Roehrig JT, Gromowski GD, Barrett AD, Fremont DH, Diamond MS. J Virol: 2007;81(23):12816-12826.

Induction of Epitope-Specific Neutralizing Antibodies against West Nile virus. Oliphant T, Nybakken GE, Austin SK, Xu Q, Bramson J, Loeb M, Throsby M, Fremont DH, Pierson TC, Diamond MS. J Virol: 2007;81(21):11828-11839.

Structural Engineering of pMHC Reagents for T Cell Vaccines and Diagnostics. Mitaksov V, Truscott SM, Lybarger L, Connolly JM, Hansen TH, Fremont DH. Chem Biol: 2007;14(8):909-922.

Antibody recognition of cell surface-associated NS1 triggers Fc-y receptor mediated phagocytosis and clearance of WNV infected cells. Kyung Min Chung, Bruce S Thompson, Daved H Fremont, and Michael S Diamond. J Virol: 2007;81(17):9551-9555.

Antigen-specific cytotoxic T lymphocytes protect against lethal West Nile virus encephalitis. Purtha WE, Myers N, Mitaksov V, Sitati E, Connolly J, Fremont DH, Hansen TH, Diamond MS. Eur J Immunol : 2007;37:1845-1854.

Disulfide bond engineering to trap peptides in the MHC class I binding groove. Truscott SM, Lybarger L, Martinko JM, Mitaksov VE, Kranz DM, Connolly JM, Fremont DH, Hansen TH. J Immunol: 2007;178(10):6280-6289.

West Nile virus nonstructural protein NS1 inhibits complement activation by binding the regulatory protein factor H. Chung KM, Liszewski MK, Nybakken G, Davis AE, Townsend RR, Fremont DH, Atkinson JP, Diamond MS. Proc Natl Acad Sci U S A: 2006;103(50):19111-19116.

Structural Determinants of Chemokine Binding by an Ectromelia Virus-Encoded Decoy Receptor. Arnold PL, Fremont DH. J Virol: 2006;80(15):7439-7449.

Crystal structure of the West Nile virus envelope glycoprotein. Nybakken GE, Nelson CA, Chen BR, Diamond MS, Fremont DH. J Virol: 2006;80(23):11467-11474.

Antibody recognition and neutralization determinants on domains I and II of West Nile Virus envelope protein. Oliphant T, Nybakken GE, Engle M, Xu Q, Nelson CA, Sukupolvi-Petty S, Marri A, Lachmi BE, Olshevsky U, Fremont DH, Pierson TC, Diamond MS. J Virol: 2006;80(24):12149-12159.

Antibodies against West Nile Virus nonstructural protein NS1 prevent lethal infection through Fc gamma receptor-dependent and -independent mechanisms. Chung KM, Nybakken GE, Thompson BS, Engle MJ, Marri A, Fremont DH, Diamond MS. J Virol: 2006;80(3):1340-1351.

Structure, expression and intracellular localization of the SARS-CoV accessory proteins 7a and 7b. Pekosz A, Schaecher SR, Diamond MS, Fremont DH, Sims AC, Baric RS. Adv Exp Med Biol: 2006;581:115-120.

Structural basis of West Nile Virus neutralization by a therapeutic antibody. Nybakken GE, Oliphant T, Johnson S, Burke S, Diamond MS, Fremont DH. Nature: 2005;437:764-769.

Development of a humanized monoclonal antibody with therapeutic potential against West Nile virus. Oliphant T, Engle M, Nybakken GE, Doane C, Johnson S, Huang L, Gorlatov S, Mehlhop E, Marri A, Chung KM, Ebel GD, Kramer LD, Fremont DH, Diamond MS. Nat Med: 2005;11(5):522-530.

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