The variable loop 3 in the envelope glycoprotein is critical for the atypical coreceptor usage of an HIV-1 strain.
The variable loop 3 in the envelope glycoprotein is critical for the atypical coreceptor usage of an HIV-1 strain.
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包膜糖蛋白中的可变环3对于非典型的HIV-1菌株使用至关重要。
DOI：
10.1371/journal.pone.0098058
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Jiang C
中科院分区：
文献类型：
--
作者：
Xiang Y;Liu W;Chen Y;Zhang C;Su W;Zhang Y;Sun J;Gao F;Jiang C
大多数HIV-1病毒株通过CCR 5和/或CXCR 4共受体进入CD 4 + T细胞。然而，我们最近发现了一种传播/创始者（T/F）病毒（ZP 6248），它有效地利用了另一种辅助受体GPR 15，而不是常用的CXCR 4和CCR 5来建立临床感染。为了了解env基因中的哪些区域对于非典型辅助受体的使用至关重要，我们产生了一组V3突变体，并确定了它们在表达不同辅助受体的GHOST细胞中的感染性。当YU 2中的可变环3（V3）被ZP 6248 V3（YU2.6248V3）替换时，嵌合体YU2.6248V3感染GPR 15+细胞，但不感染CCR 5+细胞。为了确定V3中的哪些氨基酸导致这种表型变化，将不同于亚型B共有V3的8个氨基酸中的每一个用丙氨酸取代。G306 A和S322 A突变显著降低了YU2.6248V3在GPR 15+细胞中的复制能力，而位置307、314、315、316、317和318处的所有其他丙氨酸取代完全消除了YU2.6248V3在GPR 15+细胞中的感染性。YU2.6248V3的E314 A突变和之前报道的E314 G突变一样，也使YU2.6248V3在CCR 5+细胞中具有感染性，而其他丙氨酸突变体不能感染CCR 5+细胞。这些结果表明，ZP 6248 V3中的氨基酸可能形成一种独特的构象，这对与GPR 15的相互作用至关重要，而ZP 6248 V3冠状位314位氨基酸在与CCR 5和GPR 15的相互作用中起关键作用。ZP 6248的独特表型可以作为一个模型，以了解HIV-1如何通过新的遗传变异探索不同的辅助受体库，以建立临床感染。
The majority of HIV-1 strains enter CD4+ T cells using the CCR5 and/or CXCR4 co-receptor. However, we recently identified a transmitted/founder (T/F) virus (ZP6248) that efficiently used an alternative coreceptor GPR15, rather than commonly used CXCR4 and CCR5, to establish clinical infection. To understand which regions in the env gene were critical for the atypical coreceptor usage, we generated a set of V3 mutants and determined their infectivity in GHOST cells that expressed different coreceptors. When the variable loop 3 (V3) in YU2 was replaced with the ZP6248 V3 (YU2.6248V3), the chimera YU2.6248V3 infected GPR15+ cells but not CCR5+ cells. To determine which amino acids in V3 was responsible for this phenotype change, each of the eight amino acids that differed from the subtype B consensus V3 was substituted with alanine. The G306A and S322A mutations significantly reduced the replication capacity of YU2.6248V3 in GPR15+ cells, while all other alanine substitutions at positions 307, 314, 315, 316, 317 and 318 completely abrogated the infectivity of YU2.6248V3 in GPR15+ cells. The E314A mutation, as the E314G mutation reported before, also rendered the YU2.6248V3 infectious in CCR5+ cells, while none of other alanine mutants could infect CCR5+ cells. These results demonstrated that amino acids in ZP6248 V3 might form a unique conformation that was critical for the interaction with GPR15 while the amino acids at position 314 in the V3 crown of ZP6248 played a key role in interaction with both CCR5 and GPR15. The unique phenotypes of ZP6248 can serve as a model to understand how HIV-1 explores the diverse coreceptor reservoir through novel genetic variants to establish clinical infection.
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