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BIOLOGIC PROPERTIES OF DENGUE VIRUSES FOLLOWING SERIAL PASSAGE IN PRIMARY DOG KIDNEY CELLS: STUDIES AT THE UNIVERSITY OF HAWAII

Serial passage at low dilution of seven different wild-type dengue (DEN) viruses into primary dog kidney (PDK) cell cultures placed selective pressure that resulted in the following changes from parental phenotype: smaller plaques in LLC-MK2 cells, absent plaque formation in green monkey kidney cells, lack of a cytopathic effect in LLC-MK2 cells, shut-off of virus replication at high temperatures (temperature sensitivity), reduced virulence for rhesus monkeys manifested by reduced or absent viremia and/or absence of a secondary-type antibody response following homotypic challenge, and progressive increase in the mean day of death following intracerebral inoculation of sucking mice. Two DEN-1 strains showed most of these changes by the 15th PDK passage. Only one of two DEN-2 strains studied was carried to the 50th PDK passage at the University of Hawaii. For the latter strain, both the temperature of viral replicative shutoff and mouse neurovirulence were reduced. Three DEN-4 strains showed similar late-passage biologic marker changes. The observations made, although not exhaustive, provide laboratory correlates for virus strains that have shown reduced virulence but retained immunogenicity in humans. Candidate human vaccines have been prepared from five of the studied strains: DEN-1 (16007) at PDK 13, DEN-2 (16681 and S-16803) at PDK 50 or above, and DEN-4 (1036 and 341750) at PDK 48 and 20, respectively.

Acknowledgments: Thanks are due to Laddawan Srisukonth, Ravithat Putvatana, Suwanna Vithanomsat, C. N. Venkateshan, and Kay Larsen for technical support, to Dr. Leon Rosen for providing the original viremic sera for DEN-2 (S16803) and DEN-3 (40957), to Dr. Duane J. Gubler for providing infected Aedes aegypti suspensions containing DEN-1 (1009) and DEN-4 (1036), and to Drs. Leon Rosen and Robert Tesh for amplifying viruses by mosquito inoculations.

Financial support: This work was supported by grants HS-8011, 8140 and 8304 from the Rockefeller Foundation and Contract DADA 17-69-C9146 from the U.S. Army Medical Research and Development Command.

^* Deceased.

Author’s address: Scott B. Halstead, Department of Preventive Medicine and Biometrics, Uniformed Services University of Health Sciences, 5824 Edson Lane, North Bethesda, MD 20852, Fax: 301-984-8042, E-mail: halsteads{at}erols.com.

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