Mutations conferring resistance to human immunodeficiency virus type 1 fusion inhibitors are restricted by gp4l and rev-responsive element functions
Mutations conferring resistance to human immunodeficiency virus type 1 fusion inhibitors are restricted by gp4l and rev-responsive element functions
复制标题
DOI：
10.1128/jvi.79.2.764-770.2005
复制
发表时间：
2005-01-01
影响因子：
5.4
通讯作者：
Matsuoka, M
中科院分区：
文献类型：
--
作者：
Nameki, D;Kodama, E;Matsuoka, M
人类免疫缺陷病毒（HIV）包膜蛋白gp 41在HIV融合中起着关键作用。gp 41衍生肽T-20有效抑制HIV融合，目前已被批准用于治疗HIV感染者。虽然已经报道了耐药变体，但耐药机制仍有待确定。为了详细阐明该机制，我们在体外产生了对C34（一种源自gp 41羧基末端七肽重复序列（C-HR）的肽）具有抗性的变体。抗性变体在gp 120中具有5个氨基酸的缺失，并且在gp 41中具有总共7个氨基酸的取代。结合试验显示，N-末端七肽重复序列（N-HR）中的137 K取代损害了C34的结合，而C-HR中的N126 K取代增强了与突变的N-HR的结合，表明这两种突变直接参与了耐药性。另一方面，A30和D36的取代似乎是二级突变，在Rev-响应元件（RRE）中彼此互补，并且同时突变以维持RRE的二级结构，该二级结构被137处的突变损害。因此，HIV通过直接与C34相互作用的N-HR突变获得对C34的抗性。然而，由于该区域也编码RRE，因此需要额外的突变来维持病毒复制。这些结果表明，HIV融合是HIV化疗的有吸引力的靶点之一。
One of the human immunodeficiency virus (HIV) envelope proteins, gp41, plays a key role in HIV fusion. A gp41-derived peptide, T-20, efficiently inhibits HIV fusion and is currently approved for treatment of HIV-infected individuals. Although resistant variants have been reported, the mechanism of the resistance remains to be defined. To elucidate the mechanism in detail, we generated variants resistant to C34, a peptide derived from the gp41 carboxyl terminus heptad repeat (C-HR) in vitro. The resistant variants had a 5-amino-acid deletion in gp120 and a total of seven amino acid substitutions in gp41. Binding assays revealed that an 137K substitution in the N-terminal heptad repeat (N-HR) impaired the binding of C34, whereas an N126K substitution in the C-HR enhanced the binding to mutated N-HR, indicating that both mutations were directly involved in resistance. On the other hand, substitutions for A30 and D36 seemed to be secondary mutations, located complementary to each other in the Rev-responsive element (RRE), and were mutated simultaneously to maintain the secondary structure of the RRE that was impaired by the mutations at 137. Thus, HIV acquired resistance to C34 by mutations in N-HR, which directly interacted with C34. However, since this region also encoded the RRE, additional mutations were required to maintain viral replication. These results suggest that HIV fusion is one of the attractive targets for HIV chemotherapy.