Determinants of CD4 independence for a human immunodeficiency virus type 1 variant map outside regions required for coreceptor specificity
Determinants of CD4 independence for a human immunodeficiency virus type 1 variant map outside regions required for coreceptor specificity
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DOI：
10.1128/jvi.73.12.10310-10319.1999
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发表时间：
1999-12-01
影响因子：
5.4
通讯作者：
Hoxie, JA
中科院分区：
文献类型：
--
作者：
LaBranche, CC;Hoffman, TL;Hoxie, JA
尽管人类免疫缺陷病毒（HIV）感染通常需要病毒包膜糖蛋白（Env）、CD 4和趋化因子受体之间的相互作用，但已经描述了HIV和猿免疫缺陷病毒的CD 4非依赖性分离株，这种表型的结构基础和潜在机制尚不清楚。我们已经推导出HIV-1/IIIB的变体，称为IIIBx，获得了利用CXCR 4而不利用CD 4的能力。该病毒感染CD 4阴性T和B细胞，并与仅表达人CXCR 4的鼠3 T3细胞融合。功能IIIBx env克隆表现出几个突变相比，CD 4依赖性HXBc 2 env，包括五个糖基化位点的显着损失。通过构建与HXBc 2的env嵌合体，CD 4独立性的决定因素显示出映射到V1/V2和V3高变环之外，这决定了趋化因子受体的特异性，并且至少部分地在gp 120核心上的区域内，该区域涉及形成保守的趋化因子受体结合位点。我们还鉴定了C4结构域中的点突变，其可以使IIIBx env克隆完全依赖于CD 4。跨膜蛋白（TM）中的突变也是CD 4独立性所需的。值得注意的是，当CCR 5-嗜性Env的V3环取代IIIBx Env时，发现所得嵌合体利用CCR 5但保持不依赖于CD 4。这些发现表明，趋化因子受体特异性的Env决定簇不同于介导该受体用于细胞融合的CD 4非依赖性使用的决定簇，并为Env与趋化因子受体相互作用中的多个步骤提供了功能证据。L，霍夫曼，C，C，LaBranche，W Zhang，G，Canziani，J.罗宾逊，I. Chaiken，J. A Hoxie，and R W. Doms，Proc. Natl，Acad，Sci. USA 96：6359-6364，1999），该研究的发现提示了用于疫苗目的的衍生和设计具有暴露的趋化因子受体结合位点的Env的新方法。
Although infection by human immunodeficiency virus (HIV) typically requires an interaction between the viral envelope glycoprotein (Env), CD4, and a chemokine receptor, CD4-independent isolates of HIV and simian immunodeficiency virus have been described, The structural basis and underlying mechanisms for this phenotype are unknown, We have derived a variant of HIV-1/IIIB, termed IIIBx, that acquired the ability to utilize CXCR4 without CD4. This virus infected CD4-negative T and B cells and fused with murine 3T3 cells that expressed human CXCR4 alone. A functional IIIBx env clone exhibited several mutations compared to the CD4-dependent HXBc2 env, including the striking loss of five glycosylation sites. By constructing env chimeras with HXBc2, the determinants for CD4 independence were shown to map outside the V1/V2 and V3 hypervariable loops, which determine chemokine receptor specificity, and at least partly within an area on the gp120 core that has been implicated in forming a conserved chemokine receptor binding site. We also identified a point mutation in the C4 domain that could render the IIIBx env clone completely CD4 dependent, Mutations in the transmembrane protein (TM) were also required for CD4 independence. Remarkably, when the V3 loop of a CCR5-tropic Env was substituted for the IIIBx Env, the resulting chimera was found to utilize CCR5 but remained CD4 independent. These findings show that Env determinants for chemokine receptor specificity are distinct from those that mediate CD4-independent use of that receptor for cell fusion and provide functional evidence for multiple steps in the interaction of Env with chemokine receptors, Combined with our observation that the conserved chemokine receptor binding site on gp120 is more exposed on the IIIBx gp120 (T. L, Hoffman, C, C, LaBranche, W Zhang, G, Canziani, J. Robinson,I. Chaiken, J. A Hoxie, and R W. Doms, Proc. Natl, Acad, Sci. USA 96:6359-6364, 1999), the findings from this study suggest novel approaches to derive and design Envs with exposed chemokine receptor binding sites for vaccine purposes.