Sequential broadening of CTL responses in early HIV-1 infection is associated with viral escape.
Sequential broadening of CTL responses in early HIV-1 infection is associated with viral escape.
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DOI：
10.1371/journal.pone.0000225
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发表时间：
2007-02-21
期刊：
影响因子：
3.7
通讯作者：
Nixon DF
中科院分区：
文献类型：
--
作者：
Karlsson AC;Iversen AK;Chapman JM;de Oliviera T;Spotts G;McMichael AJ;Davenport MP;Hecht FM;Nixon DF
抗原特异性CTL反应被认为在遏制HIV-1感染中起着核心作用，但在疾病进展过程中，反应的大小和/或广度与病毒载量变化之间没有一致的相关性。我们对11名未经治疗的HLA-A2阳性个体进行了纵向CTL反应和HIV-1进化的详细调查。一部分患者出现了广泛的反应，这些反应选择了Gag、Pol和Nef中一致的B表位变异，这表明ctl诱导的HIV-1在群体水平上的适应。随着时间的推移，与没有发生病毒逃逸突变的患者相比，发生病毒逃逸突变和广泛的自体CTL反应的患者在感染的第一年病毒载量显著增加。CTL反应的持续动态发展与病毒从暂时有效的免疫反应中逃逸有关。我们的研究结果表明，广泛的CTL反应通常代表病毒CTL逃逸留下的足迹，而不是有效的免疫控制，并有助于解释早期未能显示CTL反应广度与病毒载量之间关联的发现。我们的研究结果还表明，CTL压力有助于维持共识病毒序列的某些元素，这可能代表病毒从常见的hla限制性CTL反应中逃逸。HIV进化以逃避受普通HLA类型限制的CTL反应的能力突出了开发有效的基于CTL的疫苗所面临的挑战。
Antigen-specific CTL responses are thought to play a central role in containment of HIV-1 infection, but no consistent correlation has been found between the magnitude and/or breadth of response and viral load changes during disease progression. We undertook a detailed investigation of longitudinal CTL responses and HIV-1 evolution beginning with primary infection in 11 untreated HLA-A2 positive individuals. A subset of patients developed broad responses, which selected for consensus B epitope variants in Gag, Pol, and Nef, suggesting CTL-induced adaptation of HIV-1 at the population level. The patients who developed viral escape mutations and broad autologous CTL responses over time had a significantly higher increase in viral load during the first year of infection compared to those who did not develop viral escape mutations. A continuous dynamic development of CTL responses was associated with viral escape from temporarily effective immune responses. Our results suggest that broad CTL responses often represent footprints left by viral CTL escape rather than effective immune control, and help explain earlier findings that fail to show an association between breadth of CTL responses and viral load. Our results also demonstrate that CTL pressures help to maintain certain elements of consensus viral sequence, which likely represent viral escape from common HLA-restricted CTL responses. The ability of HIV to evolve to escape CTL responses restricted by a common HLA type highlights the challenges posed to development of an effective CTL-based vaccine.
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