Ragon Institute of MGH, MIT, Charlestown, Massachusetts, USA.
AIDS. 2010 Jun 19;24(10):1425-35. doi: 10.1097/QAD.0b013e32833a2b5b.
We sought to identify immunologic and virologic correlates of spontaneous viral control among long-term survivors of perinatal HIV infection expressing the protective human leukocyte antigen (HLA)-B57 allele.
The frequency, epitope specificity, and functional attributes of HIV-specific T cells and sequence variation within B57-restricted epitopes were compared between 'spontaneous controllers' who maintained normal CD4 percentages and viral loads less than 3000 copies/ml without antiretroviral therapy, and 'treated progressors' who had initiated HAART.
Recognition of HIV optimal epitopes was assessed by interferon gamma (IFNgamma) enzyme-linked immunosorbent spot. Functional characterization of CD8 cells targeting B57 epitopes was performed by staining for cytokine production (intracellular IFNgamma, interleukin-2, tumor necrosis factor alpha) and degranulation. Sequencing of autologous RNA was performed to determine the prevalence of viral escape mutations within B57-restricted epitopes and associated compensatory mutations.
HLA-B57 remained immunodominant during chronic infection in both controllers and progressors, but controllers recognized fewer epitopes and targeted epitopes within Gag and reverse transcriptase only, whereas progressors demonstrated a broader response targeting additional proteins. No individual epitope was targeted more frequently by spontaneous controllers. CD8 cytokine production patterns were heterogeneous among individuals and even among different epitopes in the same individual and did not correlate with spontaneous viral control. Extensive sequence variation within B57 epitopes was observed in both groups, but only progressors displayed additional capsid mutations that are known to offset the viral fitness cost of B57-driven immune escape.
Among HLA-B57-positive long-term survivors, spontaneous control of viremia is not associated with a qualitatively or quantitatively superior T-cell response, but with uncompensated fitness-attenuating mutations in the viral capsid.
我们旨在确定在表达保护性人类白细胞抗原（HLA）-B57 等位基因的围产期 HIV 感染长期幸存者中，自发性病毒控制的免疫和病毒学相关性。
比较未接受抗逆转录病毒治疗（ART）的“自发性控制者”（其 CD4 百分比正常，病毒载量低于 3000 拷贝/ml）和“治疗进展者”（其已开始接受高效抗逆转录病毒治疗（HAART））之间，HIV 特异性 T 细胞的频率、表位特异性和功能属性以及 B57 限制性表位内的序列变异。
通过干扰素γ（IFNγ）酶联免疫斑点法评估对 HIV 最佳表位的识别。通过染色细胞因子产生（细胞内 IFNγ、白细胞介素-2、肿瘤坏死因子-α）和脱颗粒来对针对 B57 表位的 CD8 细胞进行功能特征分析。通过自身体外 RNA 测序来确定 B57 限制性表位内的病毒逃逸突变的流行率以及相关的补偿性突变。
在慢性感染中，HLA-B57 在控制器和进展者中仍然具有免疫优势，但控制器识别的表位较少，仅针对 gag 和逆转录酶中的表位，而进展者则针对其他蛋白显示出更广泛的反应。没有个体表位被自发性控制器更频繁地靶向。CD8 细胞因子产生模式在个体之间甚至在同一个体的不同表位之间都是异质的，并且与自发性病毒控制无关。在两组中都观察到 B57 表位内的广泛序列变异，但只有进展者显示了额外的衣壳突变，这些突变已知会抵消 B57 驱动的免疫逃逸对病毒适应性的影响。
在 HLA-B57 阳性的长期幸存者中，病毒血症的自发性控制与定性或定量上更优越的 T 细胞反应无关，而是与病毒衣壳中未补偿的适应性降低突变有关。
