Structural basis for coreceptor selectivity by the HIV type 1 V3 loop
Structural basis for coreceptor selectivity by the HIV type 1 V3 loop
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DOI：
10.1089/aid.2006.0130
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发表时间：
2007-03-01
影响因子：
1.5
通讯作者：
Zolla-Pazner, Susan
中科院分区：
文献类型：
--
作者：
Cardozo, Timothy;Kimura, Tetsuya;Zolla-Pazner, Susan
HIV-1表面糖蛋白gp 120的第三可变区（V3）在病毒包膜与细胞表面趋化因子受体的相互作用中起着核心作用，触发膜融合和病毒进入人淋巴细胞和巨噬细胞。CXCR 4和CCR 5趋化因子受体分别被“X4-tropic”和“R5-tropic”病毒使用。最近，V3环的冠显示与CXC和CC趋化因子（分别为CXCR 4和CCR 5的天然配体）中的β 2-β 3环具有密切的结构同源性。这种同源性可以作为基础的3D分子建模的V3环的主要分离物，其辅助受体的使用实验定义。模型揭示了V3表面上与辅助受体使用相关的带电“补丁”。该V3表面补丁在X4嗜性病毒中带正电荷，在R5嗜性病毒中带负电荷或中性，并且由两个氨基酸形成，在位置11和位置24或25;氨基酸11和24或11和25在3D空间中彼此接触。先前已知位置11和25处的残基影响辅助受体的使用，并且这两个位置处的残基的电荷通常用于预测病毒嗜性。然而，我们发现使用残基11、24和25的电荷来鉴定X4或R5向性的预测值比仅使用残基11和25的电荷得到改善。因此，数据提出了一个新的“11/ 24/25规则”：在位置11、24或25处的带正电荷的氨基酸定义X4;否则定义R5。该规则对217种病毒的总体预测值为94%，这些病毒的嗜性已通过实验确定为X4或R5。这些结果对HIV治疗剂、疫苗和监测疾病进展的策略的设计具有额外的意义。
The third variable region (V3) of the HIV-1 surface glycoprotein, gp120, plays a central role in the interaction of the virus envelope with the cell surface chemokine receptors, triggering membrane fusion and virus entry into human lymphocytes and macrophages. The CXCR4 and CCR5 chemokine receptors are used by "X4-tropic" and "R5-tropic" viruses, respectively. Recently, the crown of the V3 loop was shown to bear a close structural homology to the beta 2-beta 3 loop in the CXC and CC chemokines, the natural ligands of CXCR4 and CCR5, respectively. This homology can serve as the foundation for 3D molecular modeling of the V3 loops from primary isolates whose coreceptor usage was experimentally defined. The modeling revealed a charged "patch" on the surface of V3 that correlates with coreceptor usage. This V3 surface patch is positively charged in X4-tropic viruses and negatively charged or neutral in R5-tropic viruses, and is formed by two amino acids, at position 11 and at position 24 or 25; amino acids 11 and 24 or 11 and 25 contact each other in 3D space. Residues at positions 11 and 25 were known previously to influence coreceptor usage, and the charge of the residues at these two positions is often used to predict viral tropism. However, we found that the predictive value of using the charge of residues 11, 24, and 25 to identify X4 or R5 tropism was improved over using only the charge of residues 11 and 25. Thus, the data suggest a new "11/ 24/25 rule": a positively charged amino acid at position 11, 24, or 25 defines X4; otherwise R5. This rule gave an overall predictive value of 94% for 217 viruses whose tropism had been determined experimentally as either X4 or R5. The results have additional implications for the design of HIV therapeutics, vaccines, and strategies for monitoring disease progression.