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Journal of Virology, September 2009, p. 8638-8645, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00581-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Humanized Mice Show Clinical Signs of Dengue Fever according to Infecting Virus Genotype {triangledown} ,{dagger}

Javier Mota and Rebeca Rico-Hesse*

Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, Texas

Received 20 March 2009/ Accepted 9 June 2009

We demonstrated that the infection of humanized NOD-scid IL2r{gamma} null mice with different strains (representing the four genotypes) of dengue virus serotype 2 (DEN-2) can induce the development of human-like disease, including fever, viremia, erythema, and thrombocytopenia. Newborn mice were irradiated and received transplants by intrahepatic inoculation of human cord blood-derived hematopoietic progenitor cells (CD34+). After 6 weeks, mouse peripheral blood was tested by flow cytometry to determine levels of human lymphocytes (CD45+ cells); rates of reconstitution ranged from 16 to 80% (median, 52%). Infection (with approximately 106 PFU, the equivalent of a mosquito bite) of these humanized mice with eight low-passage-number strains produced a high viremia extending to days 12 to 18 postinfection. We observed a significant decrease in platelets at day 10 in most of the mice and an increase in body temperature (fever) and erythema (rash) in comparison with humanized mice inoculated with cell culture medium only. Comparison of Southeast (SE) Asian and other genotype viruses (American, Indian, and West African) in this model showed significant differences in magnitude and duration of viremia and rash, with the SE Asian viruses always being highest. Indian genotype viruses produced lower viremias and less thrombocytopenia than the others, and West African (sylvatic) viruses produced the shortest periods of viremia and the lowest rash measurements. These results correlate with virulence and transmission differences described previously for primary human target cells and whole mosquitoes and may correlate with epidemiologic observations around the world. These characteristics make this mouse model ideal for the study of dengue pathogenesis and the evaluation of vaccine attenuation and antivirals.

* Corresponding author. Mailing address: Department of Virology and Immunology, Southwest Foundation for Biomedical Research, 7620 NW Loop 410, San Antonio, TX 78227. Phone: (210) 258-9681. Fax: (210) 670-3329. E-mail: rricoh{at}sfbr.org

{triangledown} Published ahead of print on 17 June 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, September 2009, p. 8638-8645, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00581-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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