Pancera Marie, Zhou Tongqing, Druz Aliaksandr, Georgiev Ivelin S, Soto Cinque, Gorman Jason, Huang Jinghe, Acharya Priyamvada, Chuang Gwo-Yu, Ofek Gilad, Stewart-Jones Guillaume B E, Stuckey Jonathan, Bailer Robert T, Joyce M Gordon, Louder Mark K, Tumba Nancy, Yang Yongping, Zhang Baoshan, Cohen Myron S, Haynes Barton F, Mascola John R, Morris Lynn, Munro James B, Blanchard Scott C, Mothes Walther, Connors Mark, Kwong Peter D
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
HIV-Specific Immunity Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature. 2014 Oct 23;514(7523):455-61. doi: 10.1038/nature13808. Epub 2014 Oct 8.
The human immunodeficiency virus type 1 (HIV-1) envelope (Env) spike, comprising three gp120 and three gp41 subunits, is a conformational machine that facilitates HIV-1 entry by rearranging from a mature unliganded state, through receptor-bound intermediates, to a post-fusion state. As the sole viral antigen on the HIV-1 virion surface, Env is both the target of neutralizing antibodies and a focus of vaccine efforts. Here we report the structure at 3.5 Å resolution for an HIV-1 Env trimer captured in a mature closed state by antibodies PGT122 and 35O22. This structure reveals the pre-fusion conformation of gp41, indicates rearrangements needed for fusion activation, and defines parameters of immune evasion and immune recognition. Pre-fusion gp41 encircles amino- and carboxy-terminal strands of gp120 with four helices that form a membrane-proximal collar, fastened by insertion of a fusion peptide-proximal methionine into a gp41-tryptophan clasp. Spike rearrangements required for entry involve opening the clasp and expelling the termini. N-linked glycosylation and sequence-variable regions cover the pre-fusion closed spike; we used chronic cohorts to map the prevalence and location of effective HIV-1-neutralizing responses, which were distinguished by their recognition of N-linked glycan and tolerance for epitope-sequence variation.
1型人类免疫缺陷病毒（HIV-1）包膜（Env）刺突由三个gp120和三个gp41亚基组成，是一种构象机器，通过从成熟的未结合配体状态，经受体结合中间体，重排为融合后状态来促进HIV-1进入。作为HIV-1病毒粒子表面唯一的病毒抗原，Env既是中和抗体的靶点，也是疫苗研发的重点。在此，我们报告了通过抗体PGT122和35O22捕获的处于成熟封闭状态的HIV-1 Env三聚体的3.5埃分辨率结构。该结构揭示了gp41的融合前构象，表明了融合激活所需的重排，并定义了免疫逃逸和免疫识别的参数。融合前的gp41通过四个螺旋环绕gp120的氨基末端和羧基末端链，形成一个膜近端环，通过将融合肽近端的甲硫氨酸插入gp41-色氨酸扣中来固定。进入所需的刺突重排包括打开扣并排出末端。N-连接糖基化和序列可变区覆盖融合前的封闭刺突；我们利用慢性感染队列绘制了有效的HIV-1中和反应的流行率和位置，这些反应通过其对N-连接聚糖的识别和对表位序列变异的耐受性来区分。
