Structural and biochemical insights into the V/I505T mutation found in the EIAV gp45 vaccine strain

文献类型： 外文期刊

第一作者： Du, Jiansen

作者： Du, Jiansen;Ma, Jing;Wang, Jianxin;Liu, Fang;Qiao, Wentao;Liu, Xinqi;Wang, Xuefeng;Qin, Yuyin;Zhu, Chunhui;Zhou, Jianhua;Shao, Yiming;Shao, Yiming

作者机构：

关键词： EIAV;gp45;Crystal structure;Stability;Vaccine strain;Heptad repeat;Pre-fusion conformation;Replication

期刊名称：RETROVIROLOGY （ 影响因子：4.602； 五年影响因子：4.199 ）

ISSN： 1742-4690

年卷期： 2014 年 11 卷

页码：

收录情况： SCI

摘要： Background: The equine infectious anemia virus (EIAV) is a lentivirus of the Retrovirus family, which causes persistent infection in horses often characterized by recurrent episodes of high fever. It has a similar morphology and life cycle to the human immunodeficiency virus (HIV). Its transmembrane glycoprotein, gp45 (analogous to gp41 in HIV), mediates membrane fusion during the infection. However, the post-fusion conformation of EIAV gp45 has not yet been determined. EIAV is the first member of the lentiviruses for which an effective vaccine has been successfully developed. The attenuated vaccine strain, FDDV, has been produced from a pathogenic strain by a series of passages in donkey dermal cells. We have previously reported that a V/I505T mutation in gp45, in combination with other mutations in gp90, may potentially contribute to the success of the vaccine strain. To this end, we now report on our structural and biochemical studies of the gp45 protein from both wide type and vaccine strain, providing a valuable structural model for the advancement of the EIAV vaccine. Results: We resolved crystal structures of the ecto-domain of gp45 from both the wild-type EIAV and the vaccine strain FDDV. We found that the V/I505T mutation in gp45 was located in a highly conserved d position within the heptad repeat, which protruded into a 3-fold symmetry axis within the six-helix bundle. Our crystal structure analyses revealed a shift of a hydrophobic to hydrophilic interaction due to this specific mutation, and further biochemical and virological studies confirmed that the mutation reduced the overall stability of the six-helix bundle in post-fusion conformation. Moreover, we found that altering the temperatures drastically affected the viral infectivity. Conclusions: Our high-resolution crystal structures of gp45 exhibited high conservation between the gp45/gp41 structures of lentiviruses. In addition, a hydrophobic to hydrophilic interaction change in the EIAV vaccine strain was found to modulate the stability and thermal-sensitivity of the overall gp45 structure. Our observations suggest that lowering the stability of the six-helix bundle (post-fusion), which may stabilizes the pre-fusion conformation, might be one of the reasons of acquired dominance for FDDV in viral attenuation.

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