: The long-term goals of this project are to determine the structural (RNA and/or protein) and transmission (replication in Aedes aegypti) characteristics of those dengue type 2 virus variants that have produced dengue hemorrhagic fever (DHF) in humans throughout the world. We have determined the most probable viral structures involved in increased virulence and transmission by studying patient-derived virus variants. Currently we have modified an infectious clone of dengue type 2 virus to contain these structures and developed three assay systems in which to test virus phenotype. We will attempt to correlate dengue virus replication rates in vitro and in vivo with clinical and epidemiologic observations in different geographic areas (U.S. border, Mexico, Peru, Venezuela, Brazil). The identification of these determinants could provide critical information for the design of vaccines and/or anti-virals, which are currently unavailable for dengue.
Specific aims : 1. To identify dengue virus factors responsible for increased replication in human and baboon target cells (monocytes and dendritic cells). Hypothesis: Specific viral structures are responsible for increased virus replication rates, which lead to severe disease (DHF) in certain individuals. 2. To identify dengue virus factors responsible for infection and dissemination in the natural mosquito vector from geographic regions with varying dengue epidemiology (presence or absence of DHF). Hypothesis: The mosquito vector promotes the transmission of those virus variants with increased replication rates (viremia) in the human host.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050123-04
Application #
6750183
Study Section
Special Emphasis Panel (ZRG1-TMP (01))
Program Officer
Repik, Patricia M
Project Start
2001-08-15
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$388,350
Indirect Cost
Name
Southwest Foundation for Biomedical Research
Department
Type
DUNS #
007936834
City
San Antonio
State
TX
Country
United States
Zip Code
78245
Cox, Jonathan; Mota, Javier; Sukupolvi-Petty, Soila et al. (2012) Mosquito bite delivery of dengue virus enhances immunogenicity and pathogenesis in humanized mice. J Virol 86:7637-49
Mota, Javier; Rico-Hesse, Rebeca (2011) Dengue virus tropism in humanized mice recapitulates human dengue fever. PLoS One 6:e20762
Cox, Jonathan; Brown, Heidi E; Rico-Hesse, Rebeca (2011) Variation in vector competence for dengue viruses does not depend on mosquito midgut binding affinity. PLoS Negl Trop Dis 5:e1172
Cassetti, M Cristina; Durbin, Anna; Harris, Eva et al. (2010) Report of an NIAID workshop on dengue animal models. Vaccine 28:4229-34
Vasilakis, Nikos; Cardosa, Jane; Diallo, Mawlouth et al. (2010) Sylvatic dengue viruses share the pathogenic potential of urban/endemic dengue viruses. J Virol 84:3726-7; author reply 3727-8
Sukupolvi-Petty, Soila; Austin, S Kyle; Engle, Michael et al. (2010) Structure and function analysis of therapeutic monoclonal antibodies against dengue virus type 2. J Virol 84:9227-39
Rico-Hesse, R (2010) Dengue virus virulence and transmission determinants. Curr Top Microbiol Immunol 338:45-55
Mota, Javier; Rico-Hesse, Rebeca (2009) Humanized mice show clinical signs of dengue fever according to infecting virus genotype. J Virol 83:8638-45
Rico-Hesse, Rebeca (2009) Dengue virus markers of virulence and pathogenicity. Future Virol 4:581
Rico-Hesse, Rebeca (2007) Dengue virus evolution and virulence models. Clin Infect Dis 44:1462-6

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