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MANIPULATION OF THE YELLOW FEVER VIRUS NON-STRUCTURAL GENES 2A AND 4B AND THE 3'NON-CODING REGION TO EVALUATE GENETIC DETERMINANTS OF VIRAL DISSEMINATION FROM THE AEDES AEGYPTI MIDGUT

Although much is known about the ecology, epidemiology, and molecular biology of mosquito-borne viruses, the viral factors that allow transmission by mosquitoes to humans or animals remain unknown. Using infectious clones of disseminating (Asibi) and non-disseminating (17D) yellow fever viruses (YFV), we produced chimeric viruses to evaluate the role of different viral genes in dissemination. Previously, we showed that virus produced from an infectious clone containing the structural genes of 17D in Asibi disseminated from the mosquito midgut at a rate of 31%, indicating that some genetic determinants of dissemination must lie within the non-structural (NS) protein genes or 3' non-coding region (NCR). We chose to investigate the roles of NS2A, NS4B, and the 3'NCR in YFV dissemination. Substitution of the 17D NS2A or NS4B into Asibi significantly attenuated YFV dissemination, demonstrating that this is a multigenic property. There was no difference in dissemination after substitution of the 17D 3'NCR.

Received June 28, 2006. Accepted for publication July 28, 2006.

Acknowledgments: We thank Jing H. Huang for expert technical assistance; the Protein Chemistry Laboratory of the University of Texas Medical Branch for sequencing; and Alan Barrett, Amber Engel, and Peter Mason for helpful discussions during the execution of this work.

Financial support: This work was in part supported by a Defense Advanced Research Projects Agency grant cooperative agreement N00178-02-2-9002 with the Chemical Biological Radiological Sciences and Technology Defense Branch of the Naval Surface Warfare Center and by Acambis, Inc. (Cambridge, MA). K. L. McElroy was supported by the Centers for Disease Control and Prevention Fellowship Training Program in Vector-Borne Infectious Diseases (T01/ CCT622892).

^* Address correspondence to Stephen Higgs, Department of Pathology, University of Texas Medical Branch, 2.104 Keiller, L20762, 301 University Boulevard, Galveston, TX 77555-0609. E-mail: sthiggs{at}utmb.edu

Authors’ address: Kate L. McElroy, Konstantin A. Tsetsarkin, Dana L. Vanlandingham, and Stephen Higgs, Department of Pathology, University of Texas Medical Branch, 2.104 Keiller, L20762, 301 University Boulevard, Galveston, TX 77555-0609, Telephone: 409-747-2426, Fax: 409-747-2437, E-mail: sthiggs{at}utmb.edu. Current address for Kate L. McElroy, Centers for Disease Control and Prevention Dengue Branch, 1324 Calle Cãnada, San Juan, PR 00920.

Reprint requests: Stephen Higgs, Department of Pathology, Keiller 2.104, 301 University Boulevard, Galveston, TX 77555-0609.