UCLA AIDS Institute and Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA.
J Virol. 2012 Oct;86(19):10505-16. doi: 10.1128/JVI.00102-12. Epub 2012 Jul 18.
Although HLA-B57 (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-B57.
尽管 HLA-B57（B57）与 HIV-1 感染后疾病的缓慢进展相关，但 B57 杂合子表现出广泛的结局，包括快速进展、病毒血症缓慢进展和精英控制。为了识别 B57 阳性（B57(+)）缓慢进展者和 B57(+)快速进展者之间的差异，研究主要集中在感染慢性阶段的细胞毒性 T 淋巴细胞（CTL）表型和特异性上。尽管感染早期的 CTL 反应可能对 HIV-1 疾病进展的长期速度最重要，但关于最终缓慢进展者的早期 CTL 反应的数据很少。利用多中心艾滋病队列研究（MACS），我们回顾性检查了 14 名 B57(+)个体的早期 HIV-1 特异性 CTL 反应，他们从感染后 3.5 年到超过 25 年不等的时间发展为疾病。一般来说，对结构蛋白（特别是 Gag）的表位以及任何 HIV-1 蛋白的高度保守表位的靶向范围更广，与疾病发生的时间更长相关。队列中的唯一精英控制器在 CTL 靶向和疾病发生时间的几个相关性上是一个异常值，这与精英控制通常不仅仅通过保护性 HLA 介导的 CTL 实现的报告一致。当分析单个表位的靶向时，我们发现 Gag 的 IW9（ISPRTLNAW）表位的早期 CTL 反应虽然通常处于次要地位，但与疾病进展的延迟相关。这是第一项确定 IW9 作为 HLA-B57 个体保护相关的早期 CTL 反应的研究。
