Early HLA-B☆57-Restricted CD8+ T Lymphocyte Responses Predict HIV-1 Disease Progression
Early HLA-B☆57-Restricted CD8+ T Lymphocyte Responses Predict HIV-1 Disease Progression
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DOI：
10.1128/jvi.00102-12
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发表时间：
2012-10-01
影响因子：
5.4
通讯作者：
Jamieson, Beth D.
中科院分区：
文献类型：
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作者：
Brennan, Catherine A.;Ibarrondo, F. Javier;Jamieson, Beth D.
虽然人类白细胞抗原B(STAR)57(B57)与HIV-1感染后疾病进展缓慢有关，但B57杂合子表现出广泛的结果，包括快速进展、病毒缓慢进展和精英控制。为了识别B57阳性(B57(+))慢进者和B57(+)快速进展者之间的差异，人们主要集中在慢性感染阶段的细胞毒性T淋巴细胞(CTL)表型和特异性。虽然感染后最初几个月的CTL反应可能是HIV-1疾病长期进展的最重要的因素，但关于最终进展缓慢的人的早期CTL反应的数据很少。利用多中心艾滋病队列研究(MACS)，我们回顾了14名B57(+)个体的早期HIV-1特异性CTL反应，他们的发病时间从感染后3.5年到超过25年不等。总体而言，针对结构蛋白表位，特别是GAG表位以及任何HIV-1蛋白的高度保守表位的范围更大，与疾病前的时间更长相关。队列中的单一精英控制者在CTL靶向和发病前时间的几个相关性上是一个异常值，与报告一致，即精英控制通常不是仅通过保护性的人类白细胞抗原介导的CTL实现的。当分析单个表位的靶点时，我们发现对GAG的IW9(ISPRTLNAW)表位的早期CTL反应，虽然通常是次显性的，但与疾病的延迟进展相关。这是第一项确定对IW9的早期CTL反应与人类白细胞抗原B(STAR)57携带者的保护相关的研究。
Although HLA-B(star)57 (B57) is associated with slow progression to disease following HIV-1 infection, B57 heterozygotes display a wide spectrum of outcomes, including rapid progression, viremic slow progression, and elite control. Efforts to identify differences between B57-positive (B57(+)) slow progressors and B57(+) rapid progressors have largely focused on cytotoxic T lymphocyte (CTL) phenotypes and specificities during chronic stages of infection. Although CTL responses in the early months of infection are likely to be the most important for the long-term rate of HIV-1 disease progression, few data on the early CTL responses of eventual slow progressors have been available. Utilizing the Multicenter AIDS Cohort Study (MACS), we retrospectively examined the early HIV-1-specific CTL responses of 14 B57(+) individuals whose time to development of disease ranged from 3.5 years to longer than 25 years after infection. In general, a greater breadth of targeting of epitopes from structural proteins, especially Gag, as well as of highly conserved epitopes from any HIV-1 protein, correlated with longer times until disease. The single elite controller in the cohort was an outlier on several correlations of CTL targeting and time until disease, consistent with reports that elite control is typically not achieved solely by protective HLA-mediated CTLs. When targeting of individual epitopes was analyzed, we found that early CTL responses to the IW9 (ISPRTLNAW) epitope of Gag, while generally subdominant, correlated with delayed progression to disease. This is the first study to identify early CTL responses to IW9 as a correlate of protection in persons with HLA-B(star)57.