Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, HFM-466, Bldg. 29, Room 532, 29 Lincoln Dr., Bethesda, MD 20892, USA.
J Virol. 2011 Dec;85(24):12929-38. doi: 10.1128/JVI.05391-11. Epub 2011 Oct 12.
We generated four HIV-1 cultures that are resistant to a peptide fusion inhibitor corresponding to the first heptad repeat of gp41 in order to study mechanisms of resistance and gain insights into envelope glycoprotein-mediated membrane fusion. Two genetic pathways emerged that were defined by acquisition of a specific mutation in either the first or second heptad repeat region of gp41 (HR1 or the HR2, respectively). Each pathway was enriched in mutations that clustered in either HR2 and V3 or in HR1 and residues in or near CD4 contact sites. The gp41 mutations in both pathways not only accounted for resistance to the selecting HR1 peptide but also conferred cross-resistance to HR2 peptide fusion inhibitors and enhanced the stability of the six-helix bundle formed by the self-assembly of HR1 and HR2. The gp120 mutations alone enhanced fusion but did not appear to directly contribute to resistance. The implications of these findings for resistance mechanisms and regulation of envelope-mediated fusion are discussed.
我们生成了四种对对应于 gp41 第一七肽重复的肽融合抑制剂具有抗性的 HIV-1 培养物,以便研究抗性机制并深入了解包膜糖蛋白介导的膜融合。出现了两种遗传途径,其特征是在 gp41 的第一或第二七肽重复区(分别为 HR1 或 HR2)中获得特定突变。每条途径都富含突变,这些突变聚集在 HR2 和 V3 或 HR1 以及 CD4 接触位点内或附近的残基中。两条途径中的 gp41 突变不仅解释了对选择的 HR1 肽的抗性,而且还赋予了对 HR2 肽融合抑制剂的交叉抗性,并增强了由 HR1 和 HR2 自身组装形成的六螺旋束的稳定性。单独的 gp120 突变增强了融合,但似乎并没有直接导致抗性。这些发现对包膜介导融合的抗性机制和调控的影响将进行讨论。