Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Pathog. 2011 Feb;7(2):e1002002. doi: 10.1371/journal.ppat.1002002. Epub 2011 Feb 24.
If future HIV vaccine design strategies are to succeed, improved understanding of the mechanisms underlying protection from infection or immune control over HIV replication remains essential. Increased cytotoxic capacity of HIV-specific CD8+ T-cells associated with efficient elimination of HIV-infected CD4+ T-cell targets has been shown to distinguish long-term nonprogressors (LTNP), patients with durable control over HIV replication, from those experiencing progressive disease. Here, measurements of granzyme B target cell activity and HIV-1-infected CD4+ T-cell elimination were applied for the first time to identify antiviral activities in recipients of a replication incompetent adenovirus serotype 5 (Ad5) HIV-1 recombinant vaccine and were compared with HIV-negative individuals and chronically infected patients, including a group of LTNP. We observed readily detectable HIV-specific CD8+ T-cell recall cytotoxic responses in vaccinees at a median of 331 days following the last immunization. The magnitude of these responses was not related to the number of vaccinations, nor did it correlate with the percentages of cytokine-secreting T-cells determined by ICS assays. Although the recall cytotoxic capacity of the CD8+ T-cells of the vaccinee group was significantly less than that of LTNP and overlapped with that of progressors, we observed significantly higher cytotoxic responses in vaccine recipients carrying the HLA class I alleles B27, B57 or B*58, which have been associated with immune control over HIV replication in chronic infection. These findings suggest protective HLA class I alleles might lead to better outcomes in both chronic infection and following immunization due to more efficient priming of HIV-specific CD8+ T-cell cytotoxic responses.
如果未来的 HIV 疫苗设计策略要取得成功，就仍然需要更好地理解感染保护或对 HIV 复制的免疫控制的机制。与有效清除 HIV 感染的 CD4+ T 细胞靶标相关的 HIV 特异性 CD8+ T 细胞的细胞毒性能力的增强，已被证明可以区分长期非进展者（LTNP），即那些对 HIV 复制具有持久控制能力的患者，与那些疾病进展的患者。在这里，首次应用颗粒酶 B 靶细胞活性和 HIV-1 感染的 CD4+ T 细胞清除测量来识别复制缺陷型腺病毒血清型 5（Ad5）HIV-1 重组疫苗接种者的抗病毒活性，并将其与 HIV 阴性个体和慢性感染患者进行比较，包括一组 LTNP。我们观察到，在最后一次免疫接种后中位数为 331 天，疫苗接种者中可轻易检测到 HIV 特异性 CD8+ T 细胞回忆性细胞毒性反应。这些反应的大小与疫苗接种次数无关，也与 ICS 测定确定的细胞因子分泌 T 细胞的百分比无关。尽管疫苗接种组的 CD8+ T 细胞的回忆性细胞毒性能力明显小于 LTNP，并且与进展者重叠，但我们观察到在携带 HLA Ⅰ类等位基因 B27、B57 或 B*58 的疫苗接种者中，细胞毒性反应明显更高，这些等位基因与慢性感染中对 HIV 复制的免疫控制有关。这些发现表明保护性 HLA Ⅰ类等位基因可能会导致慢性感染和免疫接种后更好的结果，因为 HIV 特异性 CD8+ T 细胞的细胞毒性反应的引发效率更高。
