Small-molecule inhibition of human immunodeficiency virus type 1 replication by specific targeting of the final step of virion maturation
Small-molecule inhibition of human immunodeficiency virus type 1 replication by specific targeting of the final step of virion maturation
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DOI：
10.1128/jvi.78.2.922-929.2004
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发表时间：
2004-01-01
影响因子：
5.4
通讯作者：
Chen, CH
中科院分区：
文献类型：
--
作者：
Zhou, J;Yuan, X;Chen, CH
尽管目前可用的人类免疫缺陷病毒 1 型 (HIV-1) 疗法有效，但仍然需要治疗 HIV-1 感染的新药。我们研究了 3-O-{3',3'-二甲基琥珀酰}-桦木酸 (DSB) 抑制 HIV-1 复制的机制。 DSB 在病毒生命周期的后期发挥作用，但不会在体外抑制 HIV-1 蛋白酶或干扰病毒组装或释放。 DSB 特异性地延迟衣壳 (CA) 和 p2 之间的 Gag 裂解，从而延迟成熟病毒核心的形成并降低 HIV-1 感染性。猿猴免疫缺陷病毒（SIV）的复制对 DSB 具有抗性；然而，携带 HIV-1 的 CA-p2 序列的嵌合 SIV 被该药物抑制，表明对 DSB 的敏感性映射到 HIV-1 Gag 蛋白的 CA-p2 区域。 HIV-1 CA-p2 裂解位点的单点突变赋予了对 DSB 的强大抵抗力，从而证实了该药物的靶点。对多种蛋白酶抑制剂具有抗药性的 HIV-1 菌株对 DSB 敏感。这些发现表明，DSB 特异性地保护 CA-p2 裂解位点，使其在病毒粒子成熟过程中免受病毒蛋白酶的处理，从而揭示了药物抑制 HIV-1 复制的新机制。
Despite the effectiveness of currently available human immunodeficiency virus type 1 (HIV-1) therapies, a continuing need exists for new drugs to treat HIV-1 infection. We investigated the mechanism by which 3-O-{3',3'-dimethylsuccinyl}-betulinic acid (DSB) inhibits HIV-1 replication. DSB functions at a late stage of the virus life cycle but does not inhibit the HIV-1 protease in vitro or interfere with virus assembly or release. DSB specifically delays the cleavage of Gag between the capsid (CA) and p2, resulting in delayed formation of the mature viral core and reduced HIV-1 infectivity. Replication of simian immunodeficiency virus (SIV) was resistant to DSB; however, a chimeric SIV carrying CA-p2 sequences from HIV-1 was inhibited by the drug, indicating that susceptibility to DSB maps to the CA-p2 region of the HIV-1 Gag protein. A single point mutation at the CA-p2 cleavage site of HIV-1 conferred strong resistance to DSB, confirming the target of the drug. HIV-1 strains that are resistant to a variety of protease inhibitors were sensitive to DSB. These findings indicate that DSB specifically protects the CA-p2 cleavage site from processing by the viral protease during virion maturation, thereby revealing a novel mechanism for pharmacologic inhibition of HIV-1 replication.