Assessment of immunologically relevant dynamic tertiary structural features of the HIV-1 V3 loop crown R2 sequence by ab initio folding.
Assessment of immunologically relevant dynamic tertiary structural features of the HIV-1 V3 loop crown R2 sequence by ab initio folding.
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DOI：
10.3791/2118
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发表时间：
2010-09-15
期刊：
影响因子：
--
通讯作者：
Cardozo, Timothy
中科院分区：
文献类型：
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作者：
Almond, David;Cardozo, Timothy
长期以来，HIV-1的抗原性多样性一直是疫苗设计的障碍，这种变异性在病毒表面包膜糖蛋白的V3环中尤为明显。我们以前提出，虽然V3环的冠是动态的和序列可变的，但在整个HIV-1病毒种群中，它被限制在一个免疫相关的β-发夹三级结构上。重要的是，在流行的HIV-1病毒中有数千种不同的V3环冠序列，这使得通过结晶学或核磁共振难以或不可能对各种病毒的趋势进行3D结构表征。我们之前成功的V3冠折叠研究使用了ICM-Pro分子建模软件包(Molsoft LLC，La Jolla，CA)中的从头算法，并表明V3环的冠，特别是从10到22位，充分受益于其侧翼茎的灵活性和长度，在很大程度上就像它是一个在溶液中自由折叠的无约束多肽。因此，对60,000多个流行的HIV-1毒株中任何一个毒株的V3环的这一部分进行快速从头折叠可能是有意义的。在这里，我们折叠R2菌株的V3环，以深入了解其独特特性的结构基础。R2带有一个罕见的V3环序列，被认为是导致该菌株对患者血清和单抗中和的敏感度极高的原因。该毒株可介导非依赖于CD4的感染，并似乎能引起广泛的中和抗体。我们展示了折叠结果的评估如何能够为将折叠中观察到的结构与R2观察到的免疫学活性联系起来提供信息。
The antigenic diversity of HIV-1 has long been an obstacle to vaccine design, and this variability is especially pronounced in the V3 loop of the virus' surface envelope glycoprotein. We previously proposed that the crown of the V3 loop, although dynamic and sequence variable, is constrained throughout the population of HIV-1 viruses to an immunologically relevant beta-hairpin tertiary structure. Importantly, there are thousands of different V3 loop crown sequences in circulating HIV-1 viruses, making 3D structural characterization of trends across the diversity of viruses difficult or impossible by crystallography or NMR. Our previous successful studies with folding of the V3 crown used the ab initio algorithm accessible in the ICM-Pro molecular modeling software package (Molsoft LLC, La Jolla, CA) and suggested that the crown of the V3 loop, specifically from positions 10 to 22, benefits sufficiently from the flexibility and length of its flanking stems to behave to a large degree as if it were an unconstrained peptide freely folding in solution. As such, rapid ab initio folding of just this portion of the V3 loop of any individual strain of the 60,000+ circulating HIV-1 strains can be informative. Here, we folded the V3 loop of the R2 strain to gain insight into the structural basis of its unique properties. R2 bears a rare V3 loop sequence thought to be responsible for the exquisite sensitivity of this strain to neutralization by patient sera and monoclonal antibodies. The strain mediates CD4-independent infection and appears to elicit broadly neutralizing antibodies. We demonstrate how evaluation of the results of the folding can be informative for associating observed structures in the folding with the immunological activities observed for R2.