Theoretical Biology, Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America.
PLoS Pathog. 2011 Sep;7(9):e1002209. doi: 10.1371/journal.ppat.1002209. Epub 2011 Sep 29.
Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413-415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.
在这里，我们从感染早期确定了 HIV-1 B 群包膜 (Env) 氨基酸特征，这些特征可能在传播时受到青睐，以及慢性感染中反复出现的突变模式，这些模式可能反映了常见的免疫逃逸途径。为了实现这一目标，我们比较了从几百名个体中通过单基因组扩增获得的数千个序列，这些个体要么在感染早期采样，要么在慢性感染中采样。样本在开始时分为形成假设和验证集，我们使用系统地扫描Env 的所有功能或结构分组的基于进化校正的统计策略来识别特征。我们在 CCR5 共受体结合区域附近、CD4 结合位点附近以及信号肽和细胞质结构域中发现了特征，这些特征可能影响Env 的表达和处理。与传播相关的两个特征模式特别有趣。第一个是最具统计学意义的特征，位于信号肽的第 12 位。第二个是在位置 413-415 失去一个 N-连接糖基化位点；最近发现该位点的存在与逃避强效和广泛中和抗体有关，这与在慢性感染期间为免疫逃避提供常见途径一致。它在早期感染中的反复缺失表明，它可能会影响传播时或病毒早期扩张时的适应性。我们确定的特征模式暗示Env 表达水平在病毒传播或早期扩张中受到选择，并且表明在适应性免疫反应之前建立感染时，当存在抗体时，慢性感染中许多个体反复出现的免疫逃避模式可能会受到选择。
