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.

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.

• Authors: Thuy Thu Bui, Meng Ling Moi, Takeshi Nabeshima, Taichiro Takemura, Trang Thu Nguyen, Linh Ngoc Nguyen, Hang Thi Thu Pham, Thi Thu Thuy Nguyen, Dao Huy Manh, Shyam Prakash Dumre, Shusaku Mizukami, Kenji Hirayama, Shigeru Tajima, Mai Thi Quynh Le, Kiyoshi Aoyagi, Futoshi Hasebe, Kouichi Morita
• Journal: The Journal of general virology (J Gen Virol) Vol. 99 Issue 8 Pg. 1044-1057 (08 2018) ISSN: 1465-2099 [Electronic] England
• PMID: 29916798 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Viral Nonstructural Proteins
• Interferons

Topics

• Aedes
• Amino Acid Substitution
• Animals
• Chlorocebus aethiops
• Dengue Virus (genetics)
• Genetic Variation
• Hep G2 Cells
• Humans
• Interferons (metabolism)
• Vero Cells
• Viral Nonstructural Proteins (genetics, physiology)
• Virus Replication (genetics, physiology)