Naturally arising HIV-1 Nef variants conferring escape from cytotoxic T lymphocytes influence viral entry co-receptor expression and susceptibility to superinfection.
Naturally arising HIV-1 Nef variants conferring escape from cytotoxic T lymphocytes influence viral entry co-receptor expression and susceptibility to superinfection.
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DOI：
10.1016/j.bbrc.2010.11.047
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发表时间：
2010-12
影响因子：
3.1
通讯作者：
P. Mwimanzi;Zafrul Hasan;Michiyo Tokunaga;H. Gatanaga;S. Oka;T. Ueno
中科院分区：
文献类型：
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作者：
P. Mwimanzi;Zafrul Hasan;Michiyo Tokunaga;H. Gatanaga;S. Oka;T. Ueno
HIV-1 Nef 是发病机制的关键因素，已知可下调 HIV 感染细胞表面的重要功能分子，包括病毒进入辅助受体 CCR5 和 CXCR4。其中一些 Nef 活性是由 Nef 中富含脯氨酸的保守区域介导的，并且该区域是细胞毒性 T 淋巴细胞 (CTL) 的高度靶向区域。在本研究中，我们询问体内 CTL 介导的选择压力下选择的 Nef 变体是否可能限制这些重要的 Nef 活性。对从日本 235 名受试者中分离出的自体 nef 序列的分析表明，位于富含脯氨酸区域的显示出氨基酸变异（例如 Arg75Thr 和 Tyr85Phe）的受试者明显多于具有 HLA-B*3501 的受试者。 CTL 测定证实这些突变使 HLA-B*3501 限制性 CTL 得以逃脱。 Arg75Thr 变体 Nef 选择性损害细胞表面的 CCR5 下调活性，但不损害 CXCR4；而 Tyr85Phe 变体 Nef 既不影响 CCR5 也不影响 CXCR4 下调活性。此外，表达Arg75Thr变体Nef的细胞显着削弱了对CCR5向性病毒重复感染的保护作用，但不影响CXCR4向性病毒的双重感染。这些结果强调了某些 Nef 特异性 CTL 在调节病毒辅助受体下调活性和防止 HIV-1 重复感染方面的重要性，为我们提供了对疫苗设计的更多见解。
HIV-1 Nef is a key factor for pathogenesis and is known to down-regulate functionally important molecules, including viral entry co-receptor CCR5 and CXCR4, from the surface of HIV-infected cells. Some of these Nef activities are mediated by the well-conserved proline-rich region of Nef, and this region is highly targeted by cytotoxic T lymphocytes (CTLs). In the present study, we asked whether Nef variants selected under CTL-mediated selective pressure in vivo may constrain these important Nef activities. The analysis of autologous nef sequences isolated from a cohort of total 235 subjects in Japan revealed that the subjects showing amino acid variations, such as Arg75Thr and Tyr85Phe, located within the proline-rich region were significantly over-represented by those having HLA-B∗3501. CTL assays corroborated that these mutations conferred escape from HLA-B∗3501-restricted CTLs. The Arg75Thr variant Nef selectively impaired CCR5, but not CXCR4, down-regulation activity from the cell surface; whereas the Tyr85Phe variant Nef affected neither CCR5 nor CXCR4 down-regulation activity. Moreover, the cells expressing the Arg75Thr variant Nef significantly impaired protection from superinfection by CCR5-tropic, but not CXCR4-tropic, viruses. These results highlighted the importance of certain Nef-specific CTLs in modulation of viral co-receptor down-regulation activity and protection from HIV-1 superinfection, providing us with additional insight into vaccine design.