Complex determinants in human immunodeficiency virus type 1 envelope gp120 mediate CXCR4-dependent infection of macrophages
Complex determinants in human immunodeficiency virus type 1 envelope gp120 mediate CXCR4-dependent infection of macrophages
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DOI：
10.1128/jvi.79.21.13250-13261.2005
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发表时间：
2005-11-01
影响因子：
5.4
通讯作者：
Goodenow, MM
中科院分区：
文献类型：
--
作者：
Ghaffari, G;Tuttle, DL;Goodenow, MM
宿主细胞范围或向性与辅助受体的使用相结合，将病毒表型定义为使用 CCR5 (M-R5) 的巨噬细胞趋向性、使用 CXCR4 (T-X4) 的 T 细胞系趋向性、或单独使用 CXCR4 或与 CCR5 组合的淋巴细胞和巨噬细胞趋向性（D-X4 或 D-R5X4）。尽管包膜 gp120 V3 对于 M-115 和 T-X4 表型来说是必要且充分的，但在双嗜性病毒的情况下，V3 作为主要表型决定因素的清晰度会降低。我们在体内评估了 D-X4 表型、发病机制和 D-X4 病毒的出现，并绘制了 gp120 中介导离体巨噬细胞使用 CXCR4 的遗传决定因素。具有 D-X4 表型的病毒准种与晚期 CD4(+)-T 细胞损耗显着相关，并与死后胸腺组织和外周血中的 M-115 或 T-X4 病毒混合。 D-X4 表型需要 gp120 中复杂的不连续遗传决定簇，包括 V3 中的带电和不带电氨基酸、V5 高变结构域以及与原型 M-R5 或 T-X4 病毒不同的新 V1/V2 区域。 D-X4 表型与 CXCR4 和 CD4 的融合和进入的有效利用相关，但与病毒粒子相关的 gp120 水平无关，表明 gp120 构象有助于细胞特异性向性。 D-X4 表型描述了一类复杂且异质的包膜，它们沿着进化连续体积累了多种氨基酸变化。与淋巴细胞谱系细胞相比，在巨噬细胞上使用 CXCR4 所需的独特 gp120 决定簇可以为开发新策略提供靶标，以阻止人类免疫缺陷病毒 1 型 X4 准种的出现。
Host cell range, or tropism, combined with coreceptor usage defines viral phenotypes as macrophage tropic using CCR5 (M-R5), T-cell-line tropic using CXCR4 (T-X4), or dually lymphocyte and macrophage tropic using CXCR4 alone or in combination with CCR5 (D-X4 or D-R5X4). Although envelope gp120 V3 is necessary and sufficient for M-115 and T-X4 phenotypes, the clarity of V3 as a dominant phenotypic determinant diminishes in the case of dualtropic viruses. We evaluated D-X4 phenotype, pathogenesis, and emergence of D-X4 viruses in vivo and mapped genetic determinants in gp120 that mediate use of CXCR4 on macrophages ex vivo. Viral quasispecies with D-X4 phenotypes were associated significantly with advanced CD4(+)-T-cell attrition and commingled with M-115 or T-X4 viruses in postmortem thymic tissue and peripheral blood. A D-X4 phenotype required complex discontinuous genetic determinants in gp120, including charged and uncharged amino acids in V3, the V5 hypervariable domain, and novel V1/V2 regions distinct from prototypic M-R5 or T-X4 viruses. The D-X4 phenotype was associated with efficient use of CXCR4 and CD4 for fusion and entry but unrelated to levels of virion-associated gp120, indicating that gp120 conformation contributes to cell-specific tropism. The D-X4 phenotype describes a complex and heterogeneous class of envelopes that accumulate multiple amino acid changes along an evolutionary continuum. Unique gp120 determinants required for the use of CXCR4 on macrophages, in contrast to cells of lymphocytic lineage, can provide targets for development of novel strategies to block emergence of X4 quasispecies of human immunodeficiency virus type 1.