Antibodies and Lentiviruses That Specifically Recognize a T Cell Epitope Derived from HIV-1 Nef Protein and Presented by HLA-C
Antibodies and Lentiviruses That Specifically Recognize a T Cell Epitope Derived from HIV-1 Nef Protein and Presented by HLA-C
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DOI：
10.4049/jimmunol.1001561
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发表时间：
2010-12-15
影响因子：
4.4
通讯作者：
Hizi, Amnon
中科院分区：
文献类型：
--
作者：
Herschhorn, Alon;Marasco, Wayne A.;Hizi, Amnon
HIV选择性地下调受感染细胞表面的HLA-A和-B，以避免被免疫系统检测到。相反，HLA-C分子对这种下调具有高度抗性。HLA-C在细胞表面的高表达水平与单核苷酸多态性相关，也与较低的病毒载量和较慢的艾滋病进展有关。这些发现有力地表明，HIV-1衍生的肽被HLA-C有效地呈递，并触发感染细胞的消除。因此，检测这些HLA-C-肽复合物的能力可用于HIV-1感染细胞的治疗靶向，并用于测量用HIV-1相关蛋白或基因免疫后候选疫苗的有效呈递。然而，HLA-C在细胞表面的低水平表达阻碍了这种复合物识别试剂的发展。在这项研究中，我们描述了一种高亲和力的人抗体的发展，特别是相互作用，在低pM浓度，与一个保守的病毒T细胞表位来自HIV-1 Nef蛋白和HLA-C。人Ab选择性地检测不同细胞上的这种复合物，并且不与仅在呈递肽中不同的对照复合物相互作用。工程化慢病毒以展示这种Ab赋予它们与Ab相同的特异性，而共表达Ab和Fas配体使慢病毒能够特异性地杀死Nef呈递细胞。具有这种特异性的抗体和假病毒很可能作为特异性靶向和杀死HIV-1感染细胞的构建模块而具有很高的价值。免疫学杂志，2010，185：7623-7632。
HIV selectively downregulates HLA-A and -B from the surfaces of infected cells to avoid detection by the immune system. In contrast, the HLA-C molecules are highly resistant to this downregulation. High expression level of HLA-C on the cell surface, which correlates with a single nucleotide polymorphism, is also associated with lower viral loads and slower progression to AIDS. These findings strongly suggest that HIV-1-derived peptides are efficiently presented by HLA-C and trigger the elimination of infected cells. Accordingly, the ability to detect these HLA-C-peptide complexes may be used for therapeutic targeting of HIV-1-infected cells and for measuring effective presentation of vaccine candidates after immunization with HIV-1-related proteins or genes. However, low level of HLA-C expression on the cell surface has impeded the development of such complex-recognizing reagents. In this study, we describe the development of a high-affinity human Ab that specifically interacts, at low pM concentrations, with a conserved viral T cell epitope derived from HIV-1 Nef protein and presented by HLA-C. The human Ab selectively detects this complex on different cells and does not interact with a control complex that differed only in the presented peptide. Engineering lentiviruses to display this Ab endowed them with the same specificity as the Ab, whereas coexpressing the Ab and Fas ligand enables the lentiviruses to kill specifically Nef-presenting cells. Abs and pseudoviruses with such specificity are likely to be highly valuable as building blocks for specific targeting and killing of HIV-1-infected cells. The Journal of Immunology, 2010, 185: 7623-7632.