Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease.
Quantitative analysis of the human immunodeficiency virus type 1 (HIV-1)-specific cytotoxic T lymphocyte (CTL) response at different stages of HIV-1 infection: differential CTL responses to HIV-1 and Epstein-Barr virus in late disease.
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DOI：
10.1084/jem.177.2.249
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发表时间：
1993-02-01
期刊：
影响因子：
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通讯作者：
Borysiewicz L
中科院分区：
文献类型：
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作者：
Carmichael A;Jin X;Sissons P;Borysiewicz L
主要组织相容性复合体 (MHC) 限制性细胞毒性 T 淋巴细胞 (CTL) 是针对人类持续性病毒感染的细胞免疫反应的一部分。对人类免疫缺陷病毒 1 型 (HIV-1) 特异性 CTL 的频率和特异性及其随时间变化的测量可能表明它们在调节 HIV-1 感染进展中的相对重要性。我们使用有限稀释分析 (LDA) 对 23 名处于 HIV-1 感染不同临床阶段的患者进行横断面研究，得出 HIV-1 特异性 CTL 前体频率的定量估计，并将其与同一患者中另一种持久性病毒（EB 病毒 [EBV]）特异性 CTL 前体的频率进行比较。使用感染 HIV-1 的自体淋巴母细胞在体外刺激外周血单核细胞 (PBMC)，并在 51Cr 释放试验中针对感染了表达三种 HIV-1 结构基因产物的重组痘苗病毒的自体和 MHC 不匹配的淋巴母细胞 B 细胞进行细胞毒性分析。在无症状的 HIV-1 感染患者中，MHC 限制性前体的频率很高（env 特异性 CTL 前体高达 73/10(6) PBMC；gag 特异性 CTL 前体高达 488/10(6) PBMC），尽管针对不同结构基因产物的相对频率因患者而异。在 CD4+ 淋巴细胞耗竭更严重（< 400/微升）的患者中，HIV-1 特异性 CTL 前体频率降低，而在大多数此类患者中，针对 EBV 的 CTL 前体频率维持在健康对照中观察到的水平。在九名患者中的三名中观察到未刺激的 PBMC 中的直接 CTL 活性，但在激活的 CTL 反应的存在与 LDA 刺激后检测到的 CTL 反应的强度之间没有发现相关性。因此，在 CD4+ 淋巴细胞计数 > 400/微升的患者中检测到所有三种 HIV-1 结构基因产物的 CTL 前体，其频率比报道的其他持久性病毒的频率高。针对 HIV-1 多种蛋白抗原的 CTL 反应可以保护患者免受表位变异的影响。在晚期 HIV-1 感染中维持 EBV 特异性 CTL 前体频率的事实表明，与疾病进展相关的 HIV-1 特异性 CTL 反应可能存在选择性损害。
Major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) are part of the cellular immune response to human persistent virus infections. Measurements of the frequency and specificity of human immunodeficiency virus type 1 (HIV-1)-specific CTL and their variation with time may indicate their relative importance in modulating the progression of HIV-1 infection. We have used limiting dilution analysis (LDA) to derive quantitative estimates of the frequency of HIV-1-specific CTL precursors in a cross-sectional study of 23 patients at different clinical stages of HIV-1 infection and to compare these with the frequency of CTL precursors specific for another persistent virus (Epstein-Barr virus [EBV]) in the same patients. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with autologous HIV-1-infected lymphoblasts and assayed for cytotoxicity in 51Cr release assays against autologous and MHC-mismatched lymphoblastoid B cells infected with recombinant vaccinia viruses expressing the three HIV-1 structural gene products. The frequency of MHC-restricted precursors was high in asymptomatic HIV-1-infected patients (env-specific CTL precursors up to 73/10(6) PBMC; gag-specific CTL precursors up to 488/10(6) PBMC), although the relative frequency against the different structural gene products varied from patient to patient. The HIV-1-specific CTL precursor frequency was reduced in patients who had more severe (< 400/microliters) CD4+ lymphocyte depletion, while in the majority of such patients the frequency of CTL precursors against EBV was maintained at levels observed in healthy controls. Direct CTL activity in unstimulated PBMC was observed in three of nine patients but no correlation was found between the presence of an activated CTL response and the magnitude of the CTL response detected after stimulation in LDA. Thus, CTL precursors were detected against all three HIV-1 structural gene products in patients with CD4+ lymphocyte counts > 400/microliters, at frequencies that are high compared with those reported for other persistent viruses. A CTL response directed against multiple protein antigens of HIV-1 may protect the patient against epitope variation. The fact that the EBV- specific CTL precursor frequencies were maintained in advanced HIV-1 infection suggests that there may be selective impairment of the HIV-1- specific CTL response associated with disease progression.