HIV-1 Glycan Density Drives the Persistence of the Mannose Patch within an Infected Individual.
HIV-1 Glycan Density Drives the Persistence of the Mannose Patch within an Infected Individual.
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DOI：
10.1128/jvi.01542-16
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发表时间：
2016-12-15
影响因子：
5.4
通讯作者：
Doores KJ
中科院分区：
文献类型：
--
作者：
Coss KP;Vasiljevic S;Pritchard LK;Krumm SA;Glaze M;Madzorera S;Moore PL;Crispin M;Doores KJ
HIV包膜糖蛋白（Env）被宿主来源的N-连接聚糖广泛修饰。病毒刺突上的高密度糖基化限制了酶促加工，导致许多加工不足的寡甘露糖型聚糖。这种广泛的糖基化不仅保护了蛋白质的保守区域免受免疫系统的影响，而且还作为抗HIV广泛中和抗体（bnAb）的靶标。为了响应宿主免疫系统，HIV聚糖盾通过影响潜在N-连接糖基化位点（PNGS）的位置和数量的突变不断演变。在这里，使用来自进化枝C感染个体（CAP 256）的纵向Env序列，我们测量了HIV感染期间转移聚糖盾对寡甘露糖型聚糖丰度的影响。通过分析一组重组CAP 256 gp 120的内在甘露糖斑块，显示出高蛋白序列变异性和PNGS数量和定位的变化，我们表明内在甘露糖斑块在HIV感染的整个过程中持续存在，并与PNGS的数量相关。聚糖密度对加工状态的这种影响也得到重组gp 120糖蛋白交叉进化枝组分析的支持。总之，这些观察结果强调了聚糖聚簇对于产生抗HIV bnAb的碳水化合物表位的重要性。在HIV感染过程中固有甘露糖斑块的持续存在进一步突出了该表位作为HIV疫苗策略的重要靶点。重要性开发HIV疫苗对于控制HIV大流行至关重要，而广泛中和抗体（bnAb）的激发可能是成功疫苗应答的关键组成部分。HIV包膜糖蛋白（Env）被一系列宿主来源的N-连接聚糖覆盖，通常称为聚糖盾。这种聚糖盾是许多最近分离的抗HIV bnAb的靶标，因此处于宿主免疫系统的恒定压力下，导致聚糖位点频率和位置的变化。本研究旨在确定这些遗传变化是否影响HIV Env上聚糖的最终加工以及病毒对中和的敏感性。我们表明，尽管在HIV感染过程中聚糖位点的定位和频率存在这种变化，但甘露糖补丁始终是一个保守的特征，使其成为HIV疫苗设计的稳定目标。
The HIV envelope glycoprotein (Env) is extensively modified with host-derived N-linked glycans. The high density of glycosylation on the viral spike limits enzymatic processing, resulting in numerous underprocessed oligomannose-type glycans. This extensive glycosylation not only shields conserved regions of the protein from the immune system but also acts as a target for anti-HIV broadly neutralizing antibodies (bnAbs). In response to the host immune system, the HIV glycan shield is constantly evolving through mutations affecting both the positions and numbers of potential N-linked glycosylation sites (PNGSs). Here, using longitudinal Env sequences from a clade C-infected individual (CAP256), we measured the impact of the shifting glycan shield during HIV infection on the abundance of oligomannose-type glycans. By analyzing the intrinsic mannose patch from a panel of recombinant CAP256 gp120s displaying high protein sequence variability and changes in PNGS number and positioning, we show that the intrinsic mannose patch persists throughout the course of HIV infection and correlates with the number of PNGSs. This effect of the glycan density on the processing state was also supported by the analysis of a cross-clade panel of recombinant gp120 glycoproteins. Together, these observations underscore the importance of glycan clustering for the generation of carbohydrate epitopes for anti-HIV bnAbs. The persistence of the intrinsic mannose patch over the course of HIV infection further highlights this epitope as an important target for HIV vaccine strategies. IMPORTANCE Development of an HIV vaccine is critical for control of the HIV pandemic, and elicitation of broadly neutralizing antibodies (bnAbs) is likely to be a key component of a successful vaccine response. The HIV envelope glycoprotein (Env) is covered in an array of host-derived N-linked glycans often referred to as the glycan shield. This glycan shield is a target for many of the recently isolated anti-HIV bnAbs and is therefore under constant pressure from the host immune system, leading to changes in both glycan site frequency and location. This study aimed to determine whether these genetic changes impacted the eventual processing of glycans on the HIV Env and the susceptibility of the virus to neutralization. We show that despite this variation in glycan site positioning and frequency over the course of HIV infection, the mannose patch is a conserved feature throughout, making it a stable target for HIV vaccine design.