Lineage-Specific Differences between Human and Simian Immunodeficiency Virus Regulation of gp120 Trimer Association and CD4 Binding
Lineage-Specific Differences between Human and Simian Immunodeficiency Virus Regulation of gp120 Trimer Association and CD4 Binding
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DOI：
10.1128/jvi.01076-12
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发表时间：
2012-09-01
影响因子：
5.4
通讯作者：
Sodroski, Joseph
中科院分区：
文献类型：
--
作者：
Finzi, Andres;Pacheco, Beatriz;Sodroski, Joseph
人类免疫缺陷病毒1型（HIV-1）和猿猴免疫缺陷病毒（SW）的gp 120和gp 41包膜糖蛋白的亚稳态构象必须保持在包膜糖蛋白三聚体的未配体状态。gp 120与主要受体CD 4的结合触发三聚体转变为开放构象，促进与CCR 5趋化因子受体的相互作用，并最终导致gp 41介导的病毒-细胞膜融合和进入。gp 120内部结构域中的拓扑层有助于gp 120-三聚体在未配体状态下的结合和CD 4结合。在这里，我们描述了HIV-1和SIVmac gp 120之间的相似性和差异。在这两种病毒中，gp 120 N/C末端和内部结构域β-夹心和第2层支持gp 120与包膜糖蛋白三聚体的非共价缔合。SIVmac gp 120内部结构域的第1层比HIV-1 gp 120的相应区域对三聚体缔合的贡献更大。另一方面，第1层在稳定HIV-1的CD 4结合构象中起重要作用，而不是SIVmac gp 120，因此有助于HIV-1与CD 4的结合。在SIVmac中，CD 4结合反而被色氨酸375增强，色氨酸375填充gp 120的Phe 43空腔。可溶性CD 4激活SIVmac依赖于色氨酸375和决定gp 120与三聚体紧密结合的第1层残基。对CD 4使用的不同生物学要求导致了HIV-1和SIV gp 120结构的谱系特异性差异，这些结构调节三聚体缔合和CD 4结合。
Metastable conformations of the gp120 and gp41 envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SW) must be maintained in the unliganded state of the envelope glycoprotein trimer. Binding of gp120 to the primary receptor, CD4, triggers the transition to an open conformation of the trimer, promoting interaction with the CCR5 chemokine receptor and ultimately leading to gp41-mediated virus-cell membrane fusion and entry. Topological layers in the gp120 inner domain contribute to gp120-trimer association in the unliganded state and to CD4 binding. Here we describe similarities and differences between HIV-1 and SIVmac gp120. In both viruses, the gp120 N/C termini and the inner domain beta-sandwich and layer 2 support the noncovalent association of gp120 with the envelope glycoprotein trimer. Layer 1 of the SIVmac gp120 inner domain contributes more to trimer association than the corresponding region of HIV-1 gp120. On the other hand, layer 1 plays an important role in stabilizing the CD4-bound conformation of HIV-1 but not SIVmac gp120 and thus contributes to HIV-1 binding to CD4. In SIVmac, CD4 binding is instead enhanced by tryptophan 375, which fills the Phe 43 cavity of gp120. Activation of SIVmac by soluble CD4 is dependent on tryptophan 375 and on layer 1 residues that determine a tight association of gp120 with the trimer. Distinct biological requirements for CD4 usage have resulted in lineage-specific differences in the HIV-1 and SIV gp120 structures that modulate trimer association and CD4 binding.