Townsley Samantha, Li Yun, Kozyrev Yury, Cleveland Brad, Hu Shiu-Lok
Department of Microbiology, University of Washington, Seattle, Washington, USA.
Department of Pharmaceutics, University of Washington, Seattle, Washington, USA.
J Virol. 2015 Oct 28;90(2):829-41. doi: 10.1128/JVI.02321-15. Print 2016 Jan 15.
HIV-1 establishes persistent infection in part due to its ability to evade host immune responses. Occlusion by glycans contributes to masking conserved sites that are targets for some broadly neutralizing antibodies (bNAbs). Previous work has shown that removal of a highly conserved potential N-linked glycan (PNLG) site at amino acid residue 197 (N7) on the surface antigen gp120 of HIV-1 increases neutralization sensitivity of the mutant virus to CD4 binding site (CD4bs)-directed antibodies compared to its wild-type (WT) counterpart. However, it is not clear if the role of the N7 glycan is conserved among diverse HIV-1 isolates and if other glycans in the conserved regions of HIV-1 Env display similar functions. In this work, we examined the role of PNLGs in the conserved region of HIV-1 Env, particularly the role of the N7 glycan in a panel of HIV-1 strains representing different clades, tissue origins, coreceptor usages, and neutralization sensitivities. We demonstrate that the absence of the N7 glycan increases the sensitivity of diverse HIV-1 isolates to CD4bs- and V3 loop-directed antibodies, indicating that the N7 glycan plays a conserved role masking these conserved epitopes. However, the effect of the N7 glycan on virus sensitivity to neutralizing antibodies directed against the V2 loop epitope is isolate dependent. These findings indicate that the N7 glycan plays an important and conserved role modulating the structure, stability, or accessibility of bNAb epitopes in the CD4bs and coreceptor binding region, thus representing a potential target for the design of immunogens and therapeutics.
N-linked glycans on the HIV-1 envelope protein have been postulated to contribute to viral escape from host immune responses. However, the role of specific glycans in the conserved regions of HIV-1 Env in modulating epitope recognition by broadly neutralizing antibodies has not been well defined. We show here that a single N-linked glycan plays a unique and conserved role among conserved glycans on HIV-1 gp120 in modulating the exposure or the stability of the receptor and coreceptor binding site without affecting the integrity of the Env in mediating viral infection or the ability of the mutant gp120 to bind to CD4. The observation that the antigenicity of the receptor and coreceptor binding sites can be modulated by a single glycan indicates that select glycan modification offers a potential strategy for the design of HIV-1 vaccine candidates.
HIV-1能够建立持续感染，部分原因在于其逃避宿主免疫反应的能力。聚糖的遮盖作用有助于掩盖一些广泛中和抗体（bNAbs）靶向的保守位点。先前的研究表明，去除HIV-1表面抗原gp120上氨基酸残基197（N7）处一个高度保守的潜在N-连接聚糖（PNLG）位点，与野生型（WT）相比，突变病毒对CD4结合位点（CD4bs）导向抗体的中和敏感性增加。然而，尚不清楚N7聚糖的作用在不同的HIV-1分离株中是否保守，以及HIV-1包膜糖蛋白（Env）保守区域中的其他聚糖是否具有类似功能。在这项研究中，我们研究了PNLGs在HIV-1 Env保守区域中的作用，特别是N7聚糖在一组代表不同进化枝、组织来源、共受体使用情况和中和敏感性的HIV-1毒株中的作用。我们证明，N7聚糖的缺失增加了不同HIV-1分离株对CD4bs和V3环导向抗体的敏感性，表明N7聚糖在掩盖这些保守表位方面发挥着保守作用。然而，N7聚糖对病毒对针对V2环表位的中和抗体敏感性的影响因分离株而异。这些发现表明，N7聚糖在调节CD4bs和共受体结合区域中bNAb表位的结构、稳定性或可及性方面发挥着重要且保守的作用，因此是免疫原和治疗药物设计的潜在靶点。
HIV-1包膜蛋白上的N-连接聚糖被认为有助于病毒逃避宿主免疫反应。然而，HIV-1 Env保守区域中特定聚糖在调节广泛中和抗体对表位识别方面的作用尚未明确界定。我们在此表明，单个N-连接聚糖在HIV-1 gp120上的保守聚糖中发挥独特且保守的作用，调节受体和共受体结合位点的暴露或稳定性，而不影响Env介导病毒感染的完整性或突变型gp120与CD4结合的能力。受体和共受体结合位点的抗原性可由单个聚糖调节这一观察结果表明，选择聚糖修饰为HIV-1候选疫苗的设计提供了一种潜在策略。
