Role of human immunodeficiency virus (HIV) type 1 envelope in the anti-HIV activity of the betulinic acid derivative IC9564
Role of human immunodeficiency virus (HIV) type 1 envelope in the anti-HIV activity of the betulinic acid derivative IC9564
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DOI：
10.1128/aac.45.1.60-66.2001
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发表时间：
2001-01-01
影响因子：
4.9
通讯作者：
Chen, CH
中科院分区：
文献类型：
--
作者：
Holz-Smith, SL;Sun, IC;Chen, CH
桦木酸衍生物 IC9564 是一种有效的抗人类免疫缺陷病毒（抗 HIV）化合物，可以抑制 HIV 初级分离株和实验室适应株。然而，该化合物并不影响猿猴免疫缺陷病毒和呼吸道合胞病毒的复制。合胞体形成测定结果表明，IC9564 阻断 EW 1 型 (HIV-1) 包膜介导的膜融合。对 IC9564 敏感病毒和 IC9564 抗性病毒之间交换包膜区域衍生的嵌合病毒的分析表明，gp120 内的区域和 gp41 N 端 25 个氨基酸（融合结构域）是药物敏感性的关键决定因素。通过开发 NL4-3 病毒的耐药突变体，在 gp120 区域内发现了两个突变，在 gp41 区域内发现了一个突变。突变是gp120中的G237R和R252K以及gp41融合结构域中的R533A。这些突变被重新引入 NL4-3 包膜中，并分析它们在 IC9564 耐药性中的作用。两种 gp120 突变均导致药物敏感性。相反，gp41 突变 (R533A) 似乎并未影响 IC9564 的敏感性。这些结果表明 HIV-1 gp120 在 IC9564 的抗 HIV-1 活性中发挥关键作用。
The betulinic acid derivative IC9564 is a potent anti-human immunodeficiency virus (anti-HIV) compound that can inhibit both HIV primary isolates and laboratory-adapted strains. However, this compound did not affect the replication of simian immunodeficiency virus and respiratory syncytial virus. Results from a syncytium formation assay indicated that IC9564 blocked EW type 1 (HIV-1) envelope-mediated membrane fusion. Analysis of a chimeric virus derived from exchanging envelope regions between IC9564-sensitive and IC9564-resistant viruses indicated that regions within gp120 and the N-terminal 25 amino acids (fusion domain) of gp41 are key determinants for the drug sensitivity. By developing a drug-resistant mutant from the NL4-3 virus, two mutations were found within the gp120 region and one was found within the gp41 region. The mutations are G237R and R252K in gp120 and R533A in the fusion domain of gp41. The mutations were reintroduced into the NL4-3 envelope and analyzed for their role in IC9564 resistance. Both of the gp120 mutations contributed to the drug sensitivity. On the contrary, the gp41 mutation (R533A) did not appear to affect the IC9564 sensitivity. These results suggest that HIV-1 gp120 plays a key role in the anti-HIV-1 activity of IC9564.