Carruth L M, Greten T F, Murray C E, Castro M G, Crone S N, Pavlat W, Schneck J P, Siliciano R F
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
AIDS Res Hum Retroviruses. 1999 Jul 20;15(11):1021-34. doi: 10.1089/088922299310539.
Development of an effective vaccine against HIV-1 will likely require the induction of a broad array of immune responses, including virus-specific CTLs and neutralizing antibodies. One promising vaccine approach involves live recombinant canarypox (CP)-based vectors (ALVAC) containing multiple HIV-1 genes. In phase I clinical trials in HIV-1-seronegative volunteers, the cumulative rate of detection of HIV-1-specific CTLs has been as high as 60-70%. In the present study, the factors associated with CTL responsiveness were evaluated in a subset of vaccinees immunized with a CP vector expressing portions of the gag, pro, and env genes of HIV-1 (ALVAC-HIV). CTL responses were detected in one of seven examined. While the responding individual had both CD4+ and CD8+ CTLs directed at multiple HIV-1 antigens, this response was not detectable 1 year after the last vaccination. In-depth characterization of "CTL nonresponders" showed that nonresponsiveness was not associated with defects in antigen processing or presentation. A generalized defect in CTL responsiveness was ruled out by parallel assays to detect CMV-specific CTLs from these same volunteers. Furthermore, HIV-1-specific memory CTLs were not detectable by peptide stimulation or by a novel technique for flow cytometric visualization of Gag epitope-specific T lymphocytes while HIV-1-seropositive donors frequently had 0.1-3% of CD8+ cells stain positively for this epitope (SLYNTVATL). Taken together, these results suggest that the lack of detectable HIV-1 CTLs in these volunteers was not due to classic MHC-linked nonresponsiveness.
开发一种有效的抗HIV-1疫苗可能需要诱导多种免疫反应，包括病毒特异性CTL和中和抗体。一种有前景的疫苗方法涉及基于重组金丝雀痘病毒（CP）的载体（ALVAC），其包含多个HIV-1基因。在HIV-1血清阴性志愿者的I期临床试验中，HIV-1特异性CTL的累积检测率高达60-70%。在本研究中，在用表达HIV-1 gag、pro和env基因部分的CP载体（ALVAC-HIV）免疫的一部分疫苗接种者中评估了与CTL反应性相关的因素。在七名受检者中有一名检测到了CTL反应。虽然有反应的个体具有针对多种HIV-1抗原的CD4+和CD8+CTL，但在最后一次接种疫苗后1年未检测到这种反应。对“CTL无反应者”的深入表征表明，无反应与抗原加工或呈递缺陷无关。通过检测这些相同志愿者的巨细胞病毒特异性CTL的平行试验排除了CTL反应性的普遍缺陷。此外，通过肽刺激或一种用于Gag表位特异性T淋巴细胞流式细胞术可视化的新技术未检测到HIV-1特异性记忆CTL，而HIV-1血清阳性供体经常有0.1-3%的CD8+细胞对该表位（SLYNTVATL）呈阳性染色。综上所述，这些结果表明这些志愿者中未检测到HIV-1 CTL并非由于经典的MHC相关无反应性。
