期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 292, 期 20, 页码 8236-8243出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M117.776419
关键词
-
资金
- Bill & Melinda Gates Foundation
- Ministry of Foreign Affairs of Denmark
- Irish Aid
- Ministry of Finance of Japan
- Ministry of Foreign Affairs of the Netherlands
- Norwegian Agency for Development Cooperation (NORAD)
- United Kingdom Department for International Development (DFID)
- United States Agency for International Development (USAID)
- International AIDS Vaccine Initiative
- Bill and Melinda Gates Foundation CAVD Grants [OPP1115782, OPP1084519]
- Bill and Melinda Gates Foundation [OPP1084519] Funding Source: Bill and Melinda Gates Foundation
Designing an effective HIV-1 envelope glycoprotein (Env) immunogen for elicitation of broadly neutralizing antibodies (bNAbs) is a challenging task because of the high sequence diversity, heavy glycosylation, and inherent meta-stability of Env. Based on the antigenic profile of recently isolated bNAbs, the rational approach to immunogen design is to make a stable version of the Env trimer, which mimics the native trimeric Env present on the viral surface. The SOSIP. 664 form of a clade A Env, BG505, yields a homogeneous and well ordered prefusion trimeric form, which maintains structural integrity and desired antigenicity. Following the same approach, we attempted to stabilize a naturally occurring efficiently cleaved clade C Env, namely 4-2.J41, isolated from an Indian patient. Although the SOSIP form of 4-2.J41 failed to produce reasonably well ordered trimers, the 4-2.J41. SOSIP. 664 Env could be stabilized in a native-like trimeric form by swapping a domain from BG505 Env to 4-2.J41 Env. Using various biochemical and biophysical means we confirmed that this engineered Env is cleaved, trimeric, and it retains its native-like quaternary conformation exposing mostly broadly neutralizing epitopes. Moreover, introduction of a disulfide bond in the bridging sheet region further stabilized the closed conformation of the Env. Thus, our 4-2.J41. SOSIP. 664 Env adds to the increasing pool of potential immunogens for a HIV-1 vaccine, particularly for clade C, which is the most prevalent in India and many other countries. Besides, the approach used to stabilize the 4-2.J41 Env may be used successfully with Envs from other HIV-1 strains as well. Additionally, a soluble native trimeric form of an efficiently cleaved membrane-bound Env, 4-2.J41, may be beneficial for immunization studies using various prime-boost strategies.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据