title: Replacement of pr gene with Japanese encephalitis virus pr using reverse genetics reduces antibody-dependent enhancement of dengue virus 2 infection.
abstract: Severe dengue is more likely found during secondary heterologous dengue virus (DENV) infection or primary infection of infants born to dengue-immune mothers and led to the hypothesis of antibody-dependent enhancement (ADE). It has been reported that pre-membrane (prM)-reactive antibodies do not efficiently neutralize DENV infection but instead potently promote ADE infection. Meanwhile, these enhancing anti-prM antibodies mainly react with the precursor (pr) peptide. To evaluate the effect of pr gene substitution on neutralization and ADE of DENV infection, a novel chimeric dengue virus (JEVpr/DENV2) was rationally constructed by replacing the DENV pr gene with Japanese encephalitis virus (JEV) pr gene, based on the full-length infectious complementary DNA (cDNA) clone of DENV2 ZS01/01. We found that chimeric JEVpr/DENV2 showed reduced virulence and good immunogenicity. In addition, anti-JEVpr/DENV2 sera showed broad cross-reactivity and efficient neutralizing activity with all four DENV serotypes and immature DENV2 (ImDENV2). Most importantly, compared with anti-DENV2 sera, anti-JEVpr/DENV2 sera showed significantly reduced enhancing activity of DENV infection in K562 cells. These results suggest that the ADE activities could be reduced by replacing the DENV pr gene with JEV pr gene. These findings may help us better understand the pathogenesis of DENV infection and provide a reference for the development of a vaccine against DENV.
authors.affiliation: Key laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Si
authors.affiliation: Key laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
authors.forename: Yayan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Key laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Guo
authors.affiliation: Key laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
authors.forename: Junmei
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Key laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
authors.forename: Danyun
authors.initials: D
authors.lastname: Fang
authors.affiliation: Key laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
authors.forename: Huijun
authors.initials: H
authors.lastname: Yan
authors.affiliation: Key laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China.
authors.forename: Gucheng
authors.initials: G
authors.lastname: Zeng
authors.affiliation: Key laboratory for Tropic Diseases Control, Ministry of Education of China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, People's Republic of China. jianglf@mail.sysu.edu.cn.
authors.forename: Lifang
authors.initials: L
authors.lastname: Jiang
mesh_terms: D000914:Antibodies, Viral / Q000276:immunology*; D019067:Antibody-Dependent Enhancement; D002460:Cell Line; D003716:Dengue Virus / Q000235:genetics* / Q000276:immunology*; D018349:Encephalitis Viruses, Japanese / Q000235:genetics*; D006801:Humans; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D059386:Reverse Genetics; D014759:Viral Envelope Proteins / Q000378:metabolism*; D014774:Virulence
chemical_list: D000914:Antibodies, Viral; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; C074932:prM protein, Flavivirus
keywords: ADE; Chimeric virus; Dengue virus; Infectious cDNA clone; prM antibodies