Connell Bridgette J, Lortat-Jacob Hugues
University of Grenoble Alpes, Institut de Biologie Structurale , Grenoble , France ; Centre National de la Recherche Scientifique, Institut de Biologie Structurale , Grenoble , France ; Commissariat à l'Énergie Atomique, Direction des Sciences du Vivant, Institut de Biologie Structurale , Grenoble , France.
Front Immunol. 2013 Nov 20;4:385. doi: 10.3389/fimmu.2013.00385.
By targeting cells that provide protection against infection, HIV-1 causes acquired immunodeficiency syndrome. Infection starts when gp120, the viral envelope glycoprotein, binds to CD4 and to a chemokine receptor usually CCR5 or CXCR4. As many microorganisms, HIV-1 also interacts with heparan sulfate (HS), a complex group of cell surface associated anionic polysaccharides. It has been thought that this binding, occurring at a step prior to CD4 recognition, increases infectivity by pre-concentrating the virion particles at the cell surface. Early work, dating from before the identification of CCR5 and CXCR4, showed that a variety of HS mimetics bind to the gp120 V3 loop through electrostatic interactions, compete with cell surface associated HS to bind the virus and consequently, neutralize the infectivity of a number of T-cell line-adapted HIV-1 strains. However, progress made to better understand HIV-1 attachment and entry, coupled with the recent identification of additional gp120 regions mediating HS recognition, have considerably modified this view. Firstly, the V3 loop from CXCR4-using viruses is much more positively charged compared to those using CCR5. HS inhibition of cell attachment is thus restricted to CXCR4-using viruses (such as T-cell line-adapted HIV-1). Secondly, studies aiming at characterizing the gp120/HS complex revealed that HS binding was far more complex than previously thought: in addition to the V3 loop of CXCR4 tropic gp120, HS interacts with several other cryptic areas of the protein, which can be induced upon CD4 binding, and are conserved amongst CCR5 and CXCR4 viruses. In view of these data, this review will detail the present knowledge on HS binding to HIV-1, with regards to attachment and entry processes. It will discuss the perspective of targeting the gp120 co-receptor binding site with HS mimetic compounds, a strategy that recently gave rise to entry inhibitors that work in the low nanomolar range, independently of co-receptor usage.
通过靶向提供抗感染保护的细胞，HIV-1导致获得性免疫缺陷综合征。当病毒包膜糖蛋白gp120与CD4以及通常为CCR5或CXCR4的趋化因子受体结合时，感染开始。与许多微生物一样，HIV-1也与硫酸乙酰肝素（HS）相互作用，硫酸乙酰肝素是一组复杂的细胞表面相关阴离子多糖。人们一直认为，这种在CD4识别之前的步骤发生的结合，通过在细胞表面预浓缩病毒粒子来增加感染性。早期的研究工作可追溯到CCR5和CXCR4被鉴定之前，研究表明，多种HS模拟物通过静电相互作用与gp120 V3环结合，与细胞表面相关的HS竞争结合病毒，从而中和许多T细胞系适应的HIV-1毒株的感染性。然而，在更好地理解HIV-1附着和进入方面取得的进展，以及最近对介导HS识别的其他gp120区域的鉴定，已经大大改变了这一观点。首先，与使用CCR5的病毒相比，使用CXCR4的病毒的V3环带更多正电荷基团。因此，HS对细胞附着的抑制作用仅限于使用CXCR4的病毒（如T细胞系适应的HIV-1）。其次，旨在表征gp120/HS复合物的研究表明，HS结合比以前认为的要复杂得多：除了CXCR4嗜性gp120的V3环外，HS还与该蛋白的其他几个隐蔽区域相互作用，这些区域可在CD4结合时被诱导，并且在CCR5和CXCR4病毒中保守。鉴于这些数据，本综述将详细介绍目前关于HS与HIV-1结合在附着和进入过程方面的知识。它将讨论用HS模拟化合物靶向gp120共受体结合位点的前景，这一策略最近产生了在低纳摩尔范围内起作用的进入抑制剂，且与共受体的使用无关。
