Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702-1201, USA.
Retrovirology. 2010 Apr 20;7:36. doi: 10.1186/1742-4690-7-36.
The maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage. Recent clinical trials demonstrated that a significant proportion of HIV-1-infected patients do not respond to BVM. A patient's failure to respond correlated with baseline polymorphisms at SP1 residues 6-8.
In this study, we demonstrate that varying levels of BVM resistance are associated with point mutations at these residues. BVM susceptibility was maintained by SP1-Q6A, -Q6H and -T8A mutations. However, an SP1-V7A mutation conferred high-level BVM resistance, and SP1-V7M and T8Delta mutations conferred intermediate levels of BVM resistance.
Future exploitation of the CA-SP1 cleavage site as an antiretroviral drug target will need to overcome the baseline variability in the SP1 region of Gag.
成熟抑制剂 bevirimat（BVM）通过阻断衣壳-间隔肽 1（CA-SP1）切割来有效抑制人类免疫缺陷病毒 1 型（HIV-1）的复制。最近的临床试验表明，相当一部分 HIV-1 感染患者对 BVM 没有反应。患者的反应失败与 SP1 残基 6-8 的基线多态性有关。
在这项研究中，我们证明了这些残基的点突变与不同水平的 BVM 耐药性相关。SP1-Q6A、-Q6H 和 -T8A 突变维持了 BVM 的敏感性。然而，SP1-V7A 突变赋予了高水平的 BVM 耐药性，而 SP1-V7M 和 T8Delta 突变赋予了中等水平的 BVM 耐药性。
未来将 CA-SP1 切割位点作为抗逆转录病毒药物靶点进行开发时，需要克服 Gag 中 SP1 区域的基线变异性。
