PNAS：艾滋病病毒外层糖分子链结构独特

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PNAS：艾滋病病毒外层糖分子链结构独特
为开发艾滋病疫苗提供了新思路

英国牛津大学网站近日发布新闻公报称，该校领导的一国际研究小组研究发现，艾滋病病毒（HIV）外层包裹的糖分子链结构独特且十分稳定，这与人体其他细胞完全不同。研究人员指出，可利用这个特点开发新型艾滋病疫苗，以使人体免疫系统能够识别易变的HIV，并对抗感染。

来自英国牛津大学、美国加州斯克里普斯研究所和马萨诸塞州波士顿Ragon研究所的研究人员组成的国际研究小组，对来自世界不同地区的HIV进行了分析。他们从各种HIV-1活体病毒样本中剥离出碳水化合物层（糖衣），在对其化学结构进行分析后发现，这种糖存在于所有的HIV-1病毒及其进化枝中，其结构是独一无二的，与人体细胞中的其他糖形式完全不同。

研究人员还发现，目前开发中的艾滋病疫苗的糖结构与HIV中的糖结构并不一样，因此可能导致这些疫苗无法完全模拟HIV。

领导此项研究的英国牛津大学克里斯·斯坎伦博士指出，病毒外层包裹的紧密糖衣被称做“碳水化合物伪装层”，因为这个糖链看起来和人体细胞外层糖链一样，一般情况下很难被免疫系统识别。而新发现表明，HIV的这种伪装是有缺陷的，HIV上糖的特殊性或许提供了攻击病毒的机会。通过疫苗配方中设置的危险信号，可以迫使免疫系统注意这种特殊的糖结构，从而识别HIV。斯坎伦博士称，一些癌症疫苗的开发就是利用了这种方法。

斯坎伦博士指出，HIV极其易变，一个HIV感染者体内病毒在一天之内的变化，比整个英国一个流感季节流感病毒的变化还要多。这种病毒易变性对于开发艾滋病疫苗来说是个不小的挑战。而发现HIV外层糖链的特殊性，将有助于找到一种开发艾滋病疫苗的新方法。

该研究成果刊发在最近一期美国《国家科学院院刊》（PNAS）上。

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Envelope glycans of immunodeficiency virions are almost entirely oligomannose antigens
Katie J. Dooresa,b,1, Camille Bonomellic,1, David J. Harveyc, Snezana Vasiljevicc, Raymond A. Dwekc, Dennis R. Burtona,b, Max Crispinc, and Christopher N. Scanlanc,2
+ Author Affiliations

aDepartment of Immunology and Microbial Science and International AIDS Vaccine Initiative Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037;
bThe Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02114; and
cOxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom
Communicated by Richard A. Lerner, The Scripps Research Institute, La Jolla, CA, June 2, 2010 (received for review April 16, 2010)

↵1K.J.D. and C.B. contributed equally to this work.

【Abstract】The envelope spike of HIV is one of the most highly N-glycosylated structures found in nature. However, despite extensive research revealing essential functional roles in infection and immune evasion, the chemical structures of the glycans on the native viral envelope glycoprotein gp120—as opposed to recombinantly generated gp120—have not been described. Here, we report on the identity of the N-linked glycans from primary isolates of HIV-1 (clades A, B, and C) and from the simian immunodeficiency virus. MS analysis reveals a remarkably simple and highly conserved virus-specific glycan profile almost entirely devoid of medial Golgi-mediated processing. In stark contrast to recombinant gp120, which shows extensive exposure to cellular glycosylation enzymes (>70% complex type glycans), the native envelope shows barely detectable processing beyond the biosynthetic intermediate Man5GlcNAc2 (<2% complex type glycans). This oligomannose (Man5–9GlcNAc2) profile is conserved across primary isolates and geographically divergent clades but is not reflected in the current generation of gp120 antigens used for vaccine trials. In the context of vaccine design, we also note that Manα1→2Man-terminating glycans (Man6–9GlcNAc2) of the type recognized by the broadly neutralizing anti-HIV antibody 2G12 are 3-fold more abundant on the native envelope than on the recombinant monomer and are also found on isolates not neutralized by 2G12. The Manα1→2Man residues of gp120 therefore provide a vaccine target that is physically larger and antigenically more conserved than the 2G12 epitope itself. This study revises and extends our understanding of the glycan shield of HIV with implications for AIDS vaccine design.