@article{mbs:/content/journal/jgv/10.1099/jgv.0.001092, author = "Bui, Thuy Thu and Moi, Meng Ling and Nabeshima, Takeshi and Takemura, Taichiro and Nguyen, Trang Thu and Nguyen, Linh Ngoc and Pham, Hang Thi Thu and Nguyen, Thi Thu Thuy and Manh, Dao Huy and Dumre, Shyam Prakash and Mizukami, Shusaku and Hirayama, Kenji and Tajima, Shigeru and Le, Mai Thi Quynh and Aoyagi, Kiyoshi and Hasebe, Futoshi and Morita, Kouichi", title = "A single amino acid substitution in the NS4B protein of Dengue virus confers enhanced virus growth and fitness in human cells in vitro through IFN-dependent host response", journal= "Journal of General Virology", year = "2018", volume = "99", number = "8", pages = "1044-1057", doi = "https://doi.org/10.1099/jgv.0.001092", url = "https://www.microbiologyresearch.org/content/journal/jgv/10.1099/jgv.0.001092", publisher = "Microbiology Society", issn = "1465-2099", type = "Journal Article", keywords = "NS4B", keywords = "variants", keywords = "Dengue virus", abstract = "Dengue virus (DENV) replication between mosquito and human hosts is hypothesized to be associated with viral determinants that interact in a differential manner between hosts. However, the understanding of inter-host viral determinants that drive DENV replication and growth between hosts is limited. Through the use of clinical isolates, we identified an amino acid variation of Ala, Met and Val at position 116 of DENV-1 NS4B. While the proportion of virus with the NS4B-116V variant remained constantly high in serial passages in a mosquito cell line, populations of the NS4B-116M and NS4B-116A variants became dominant after serial passages in mammalian cell lines. Using recombinant DENV-1 viruses, the Val to Ala or Met alteration at position NS4B-116 (rDENV-1-NS4B-116A and rDENV-1-NS4B-116M) resulted in enhanced virus growth in human cells in comparison to the clone with Val at NS4B-116 (rDENV-1-NS4B-116V). However, the reverse phenomenon was observed in a mosquito cell line. Additionally, in a human cell line, differential levels of IFN-α/β and IFN-stimulated gene expressions (IFIT3, IFI44L, OAS1) suggested that the enhanced viral growth was dependent on the ability of the NS4B protein to hamper host IFN response during the early phase of infection. Overall, we identified a novel and critical viral determinant at the pTMD3 of NS4B region that displayed differential effects on DENV replication and fitness in human and mosquito cell lines. Taken together, the results suggest the importance of the NS4B protein in virus replication and adaptation between hosts.", }