BETTY AN-YE WU-HSIEHWan, Shu-WenShu-WenWanLu, Yi-TienYi-TienLuHuang, Chia-HuiChia-HuiHuangLin, Chiou-FengChiou-FengLinAnderson, RobertRobertAndersonLiu, Hsiao-ShengHsiao-ShengLiuYeh, Trai-MingTrai-MingYehYen, Yu-TingYu-TingYenWu-Hsieh, Betty A.Betty A.Wu-HsiehLin, Yee-ShinYee-ShinLinManicassamy, BalajiBalajiManicassamy2018-09-102018-09-102014http://www.scopus.com/inward/record.url?eid=2-s2.0-84899123513&partnerID=MN8TOARShttp://scholars.lib.ntu.edu.tw/handle/123456789/384257Background: 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 DC 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. ? 2014 Wan et al.[SDGs]SDG3chimeric protein; deltaC NSI antibody; DENV NS1 antibody; DJ NS1 antibody; nonstructural protein 1; protein antibody; unclassified drug; virus antibody; NS1 protein, Dengue virus type 2; peptide fragment; virus antibody; virus protein; active immunization; amino terminal sequence; animal experiment; animal model; animal tissue; antibody response; antigen binding; article; bleeding time; carboxy terminal sequence; cell infiltration; complement system; controlled study; cross reaction; dengue; Dengue virus; disease model; endothelium cell; human; human cell; inoculation; Japanese encephalitis virus; macrophage infiltration; macrophage migration inhibition; mouse; nonhuman; passive immunization; protein structure; skin bleeding; thrombocyte; vaccination; virus inhibition; virus load; virus replication; animal; C3H mouse; dengue; drug effects; Hemorrhage; immunology; vaccination; Animals; Antibodies, Viral; Blood Platelets; Cross Reactions; Dengue; Dengue Virus; Hemorrhage; Humans; Mice, Inbred C3H; Peptide Fragments; Vaccination; Viral Nonstructural Proteins; Virus Replicationjournal article10.1371/journal.pone.0092495