Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.
Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.
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DOI：
10.1371/journal.pcbi.1000955
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发表时间：
2010-10-07
影响因子：
4.3
通讯作者：
Korber B
中科院分区：
文献类型：
--
作者：
Gnanakaran S;Daniels MG;Bhattacharya T;Lapedes AS;Sethi A;Li M;Tang H;Greene K;Gao H;Haynes BF;Cohen MS;Shaw GM;Seaman MS;Kumar A;Gao F;Montefiori DC;Korber B
对HIV-1包膜糖蛋白（Env）gp 120和gp 41的分子和抗原结构的了解稳步增加，为疫苗设计提供了重要的新见解，但很难将这些信息转化为可激发广泛中和抗体的免疫原。为了帮助弥合这一差距，我们使用遗传学校正的统计方法来鉴定来自产生有效中和抗体的人的Env中的氨基酸特征模式，假设这些Env可能具有可用于并入疫苗免疫原的共同特征。在尝试此之前，基本上作为对照，我们探索了我们的计算方法的效用，通过分析来自251个克隆病毒的Env序列来定义复杂中和表型的特征，这些克隆病毒对良好表征的gp 120特异性单克隆抗体b12的中和具有差异敏感性。我们确定了10个b12中和特征，包括7个在b12结合表面的gp 120或在V2区的gp 120，以前已被证明影响b12的敏感性。一个简单的算法的基础上的b12签名模式是预测b12的敏感性/耐药性在一个额外的盲板的57种病毒。在获得这些令人放心的结果后，我们继续应用这些相同的计算方法来定义来自HIV-1感染者的Env中的签名模式，这些HIV-1感染者具有有效的广泛中和反应。我们分析了一个棋盘式的中和数据集，其中来自69名HIV-1感染者的血清针对25种不同的Env进行了测试。鉴定了具有高中和效力和低中和效力的不同血清簇。发现从69个样品中获得的Env序列中的6个特征位置与高或低效价反应强烈相关。5个位点在CD 4诱导的辅助受体结合位点的gp 120，这表明该区域在激发广泛中和抗体反应对HIV-1的重要作用。中和抗体阻断细胞的感染，因此被认为是用疫苗引发的重要因素。HIV-1疫苗设计中的一个核心问题是HIV-1是极其可变的，并采用许多策略来避免被抗体识别。尽管如此，一个感染个体的子集会产生强有力的交叉反应性中和抗体应答。我们开发了计算策略，用于识别HIV-1包膜糖蛋白（gp 120和gp 41）突变模式与中和表型之间的相关性。我们首先应用这些方法来定义与对强效中和抗体b12的易感性相关的突变，作为一种手段来探索在b12-gp 120相互作用的充分理解的背景下将我们的计算策略应用于中和抗体表型的适当性。然后，我们在一组从HIV-1感染者中取样的包膜糖蛋白中定义了签名，这些人产生了有效或弱的中和抗体反应，假设包膜糖蛋白的共同特征在自然感染中引发良好的抗体，可能有助于作为疫苗免疫原。与有效中和抗体反应相关的特征突变集中在gp 120的辅助受体结合位点-HIV-1进入细胞的关键区域。
A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1. Neutralizing antibodies block infection of cells and thus are considered important to elicit with vaccines. A central problem in HIV-1 vaccine design is that HIV-1 is extremely variable and employs a number of strategies to avoid being recognized by antibodies. Despite this, a subset of infected individuals mounts potent, cross-reactive neutralizing antibody responses. We developed computational strategies for identifying correlations between mutational patterns in the HIV-1 envelope glycoproteins (gp120 and gp41) and neutralization phenotypes. We first applied these methods to define mutations that correlated with susceptibility to the potent neutralizing antibody b12, as a means to explore the appropriateness of applying our computational strategies to neutralizing antibody phenotypes within the well-understood context of b12-gp120 interactions. Signature sites of known importance were found. We then defined signatures in a panel of envelope glycoproteins sampled from HIV-1-infected individuals who made either potent or weak neutralizing antibody responses, with the hypothesis that common features of the envelope glycoproteins that elicit good antibodies in natural infection might be useful to incorporate as vaccine immunogens. Signature mutations associated with potent neutralizing antibody responses were concentrated in the coreceptor binding site of gp120 – a key region for HIV-1 entry into cells.
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影响因子：
3.7
作者：
Carlson J;Kadie C;Mallal S;Heckerman D
通讯作者：
Heckerman D
DOI：
10.1126/science.1175868
发表时间：
2009-11-20
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen L;Kwon YD;Zhou T;Wu X;O'Dell S;Cavacini L;Hessell AJ;Pancera M;Tang M;Xu L;Yang ZY;Zhang MY;Arthos J;Burton DR;Dimitrov DS;Nabel GJ;Posner MR;Sodroski J;Wyatt R;Mascola JR;Kwong PD
通讯作者：
Kwong PD
影响因子：
5.4
作者：
Binley, James M.;Lybarger, Elizabeth A.;Mascola, John R.
通讯作者：
Mascola, John R.
影响因子：
120.7
作者：
BELSHE, RB;GRAHAM, BS;FAST, P
通讯作者：
FAST, P
影响因子：
5.4
作者：
Abrahams, M. -R.;Anderson, J. A.;Williamson, C.
通讯作者：
Williamson, C.