This project will investigate the role of human antibodies in protection against or enhancement of infection caused by serotype 3 dengue viruses. Pre-existing heterotypic dengue antibody is a risk factor for lifethreatening severe illness, designated dengue hemorrhagic fever (DHF). Although it is well established that the induction of heterotypic dengue antibodies can predispose subjects to DHF, the molecular basis for this problem is not well understood. This issue is a major obstacle to effective development of dengue vaccines as it is not clear that tetravalent vaccine formulations can be established that always retain the immunogenicity of all four serotypes. Better knowledge of the molecular basis of antibody-mediated neutralization of infection is needed. In the work proposed in this application, we will derive large panels of human monoclonal antibodies directed to dengue virus serotype 3 from the B cells of subjects previously infected with that virus. In previous work funded by the RCE, we have developed a very reliable and robust method for generating human monoclonal antibody secretign hybridoma lines from immune donors. We will determine the genetic and structural basis for effective neutralization of dengue viruses by sequence analysis of antibodies, generation of recombinant antibodies for study of naturally occurring somatic mutations, generation of escape mutant viruses, definition of determinants of components of affinity (on and off rates), and determination of structures of immunodominant antibodies bound to viral antigens.

Public Health Relevance

This project is highly relevant to the goals of the SERCEB RCE, specifically defining important mechanisms of immunity to a virus that is a major cause of human illness (approximately 100 million febrile illnesses a year worldwide).

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZAI1-DDS-M)
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University of North Carolina Chapel Hill
Chapel Hill
United States
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Guo, Haitao; Gao, Jianmei; Taxman, Debra J et al. (2014) HIV-1 infection induces interleukin-1? production via TLR8 protein-dependent and NLRP3 inflammasome mechanisms in human monocytes. J Biol Chem 289:21716-26
Emery, Felicia D; Stabenow, Jennifer M; Miller, Mark A (2014) Efficient inactivation of Burkholderia pseudomallei or Francisella tularensis in infected cells for safe removal from biosafety level 3 containment laboratories. Pathog Dis 71:276-81
Rice, Amanda D; Adams, Mathew M; Lindsey, Scott F et al. (2014) Protective properties of vaccinia virus-based vaccines: skin scarification promotes a nonspecific immune response that protects against orthopoxvirus disease. J Virol 88:7753-63
Pop, Laurentiu M; Barman, Stephen; Shao, Chunli et al. (2014) A reevaluation of CD22 expression in human lung cancer. Cancer Res 74:263-71
Agnihothram, Sudhakar; Yount Jr, Boyd L; Donaldson, Eric F et al. (2014) A mouse model for Betacoronavirus subgroup 2c using a bat coronavirus strain HKU5 variant. MBio 5:e00047-14
Zellweger, Raphaƫl M; Eddy, William E; Tang, William W et al. (2014) CD8+ T cells prevent antigen-induced antibody-dependent enhancement of dengue disease in mice. J Immunol 193:4117-24
Zhao, Jincun; Li, Kun; Wohlford-Lenane, Christine et al. (2014) Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci U S A 111:4970-5
Krumm, Stefanie A; Yan, Dan; Hovingh, Elise S et al. (2014) An orally available, small-molecule polymerase inhibitor shows efficacy against a lethal morbillivirus infection in a large animal model. Sci Transl Med 6:232ra52
Blake, Lauren E; Garcia-Blanco, Mariano A (2014) Human genetic variation and yellow fever mortality during 19th century U.S. epidemics. MBio 5:e01253-14
de Alwis, Ruklanthi; de Silva, Aravinda M (2014) Measuring antibody neutralization of dengue virus (DENV) using a flow cytometry-based technique. Methods Mol Biol 1138:27-39

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