HIV-1 adapts to a retrocyclin with cationic amino acid substitutions that reduce fusion efficiency of grp41
HIV-1 adapts to a retrocyclin with cationic amino acid substitutions that reduce fusion efficiency of grp41
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DOI：
10.4049/jimmunol.176.11.6900
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发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Cole, Alexander M.
中科院分区：
文献类型：
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作者：
Cole, Amy L.;Yang, Otto O.;Cole, Alexander M.
Retrocyclin（RC）-101是一种阳离子theta-防御素，可抑制HIV-1进入。通过这种环状minidefensin在选择性压力下传代HIV-1（BAL）导致病毒对RC-101的敏感性仅降低5至10倍。出现的病毒分离株在其包膜糖蛋白中有三个氨基酸取代。一个位于gp 120的CD 4结合区，另一个位于gp 41的七肽重复（HR）结构域（HR 1和HR 2）。每个突变都用带正电的残基取代了电中性或负电性残基。在单轮病毒进入试验中单独或组合评价这些突变。虽然gp 120的突变不影响病毒进入，但gp 41的HR 1突变赋予了对RC-101的相对抗性。有趣的是，具有HR 2突变的包膜效率较低，并且变得共依赖于RC-101的存在来进入。HIV-1对这种阳离子宿主防御肽的适应性反应类似于细菌调节其表面或膜电荷以逃避类似宿主防御肽的反应。这些发现还表明，θ-防御素和gp 41之间的相互作用可能有助于这些环状小防御素阻止HIV-1进入靶细胞的能力。
Retrocyclin (RC)-101 is a cationic theta-defensin that inhibits HIV-1 entry. Passaging HIV-1(BAL) under selective pressure by this cyclic minidefensin resulted in only a 5- to 10-fold decrease in viral susceptibility to RC-101. Emergent viral isolates had three amino acid substitutions in their envelope glycoprotein. One was in a CD4-binding region of gp120, and the others were in the heptad repeat (HR) domains of gp41 (HR1 and HR2). Each mutation replaced an electroneutral or electronegative residue with one that was positively charged. These mutations were evaluated either alone or in combination in a single-round viral entry assay. Although the mutation in gp120 did not affect viral entry, the mutation in HR1 of gp41 conferred relative resistance to RC-101. Interestingly, the envelope with the HR2 mutation was less efficient and became codependent on the presence of RC-101 for entry. The adaptive response of HIV-1 to this cationic host defense peptide resembles the responses of bacteria that modulate their surface or membrane charge to evade analogous host defense peptides. These findings also suggest that interactions between theta-defensins and gp41 may contribute to the ability of these cyclic minidefensins to prevent HIV-1 entry into target cells.