Protection against dengue virus infection in mice by administration of antibodies against modified nonstructural protein 1.

Abstract

BACKGROUND:

Infection with dengue virus (DENV) may cause life-threatening disease with thrombocytopenia and vascular leakage which are related to dysfunction of platelets and endothelial cells. We previously showed that antibodies (Abs) against DENV nonstructural protein 1 (NS1) cross-react with human platelets and endothelial cells, leading to functional disturbances. Based on sequence homology analysis, the C-terminal region of DENV NS1 protein contains cross-reactive epitopes. For safety in vaccine development, the cross-reactive epitopes of DENV NS1 protein should be deleted or modified.

METHODOLOGY/PRINCIPAL FINDINGS:

We tested the protective effects of Abs against full-length DENV NS1, NS1 lacking the C-terminal amino acids (a.a.) 271-352 (designated ΔC NS1), and chimeric DJ NS1 consisting of N-terminal DENV NS1 (a.a. 1-270) and C-terminal Japanese encephalitis virus NS1 (a.a. 271-352). The anti-ΔC NS1 and anti-DJ NS1 Abs showed a lower binding activity to endothelial cells and platelets than that of anti-DENV NS1 Abs. Passive immunization with anti-ΔC NS1 and anti-DJ NS1 Abs reduced DENV-induced prolonged mouse tail bleeding time. Treatment with anti-DENV NS1, anti-ΔC NS1 and anti-DJ NS1 Abs reduced local skin hemorrhage, controlled the viral load of DENV infection in vivo, synergized with complement to inhibit viral replication in vitro, as well as abolished DENV-induced macrophage infiltration to the site of skin inoculation. Moreover, active immunization with modified NS1 protein, but not with unmodified DENV NS1 protein, reduced DENV-induced prolonged bleeding time, local skin hemorrhage, and viral load.

CONCLUSIONS/SIGNIFICANCE:

These results support the idea that modified NS1 proteins may represent an improved strategy for safe and effective vaccine development against DENV infection.

• Authors: Shu-Wen Wan, Yi-Tien Lu, Chia-Hui Huang, Chiou-Feng Lin, Robert Anderson, Hsiao-Sheng Liu, Trai-Ming Yeh, Yu-Ting Yen, Betty A Wu-Hsieh, Yee-Shin Lin
• Journal: PloS one (PLoS One) Vol. 9 Issue 3 Pg. e92495 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24658118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Viral
• NS1 protein, Dengue virus type 2
• Peptide Fragments
• Viral Nonstructural Proteins

Topics

• Animals
• Antibodies, Viral (immunology)
• Blood Platelets (drug effects)
• Cross Reactions (immunology)
• Dengue (prevention & control)
• Dengue Virus (immunology)
• Hemorrhage (prevention & control)
• Humans
• Mice, Inbred C3H
• Peptide Fragments (immunology)
• Vaccination
• Viral Nonstructural Proteins (immunology)
• Virus Replication (drug effects)