Dynamics of viral evolution and CTL responses in HIV-1 infection.
Dynamics of viral evolution and CTL responses in HIV-1 infection.
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DOI：
10.1371/journal.pone.0015639
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发表时间：
2011-01-20
期刊：
影响因子：
3.7
通讯作者：
Mullins JI
中科院分区：
文献类型：
--
作者：
Liu Y;McNevin JP;Holte S;McElrath MJ;Mullins JI
提高对宿主免疫反应动力学和病毒进化的理解对于有效设计HIV-1疫苗至关重要。我们全面分析了细胞毒性t淋巴细胞(CTL)-病毒表位动力学在抗逆转录病毒therapy-naïve受试者在头四年的HIV-1感染。我们发现CTL反应是顺序发展的，需要持续的抗原刺激来维持。在急性/早期感染中，CTL反应表现出强烈的选择压力，出现早，逃逸快，增殖快，占优势。尽管CTL对一些持久的表位的反应在感染的前两个月出现，但它们增殖缓慢。当CTL表位被突变变异体取代时，相应的反应立即下降，在强选择表位的情况下最迅速。通过交叉反应和新生反应对表位变异的CTL识别在整个研究期间都很常见。我们的数据表明，hiv特异性CTL反应，特别是在关键的急性/早期阶段，集中在易于逃逸的区域。CTL反应未能强烈靶向病毒的功能或结构关键区域，以及CTL反应的顺序级联，紧随其后的是病毒逃逸和相应反应的下降，可能导致缺乏可持续的病毒抑制。将早期和快速增殖的CTL集中在持久的表位上可能对HIV-1感染的持久病毒控制至关重要。
Improved understanding of the dynamics of host immune responses and viral evolution is critical for effective HIV-1 vaccine design. We comprehensively analyzed Cytotoxic T-lymphocyte (CTL)-viral epitope dynamics in an antiretroviral therapy-naïve subject over the first four years of HIV-1 infection. We found that CTL responses developed sequentially and required constant antigenic stimulation for maintenance. CTL responses exerting strong selective pressure emerged early and led to rapid escape, proliferated rapidly and were predominant during acute/early infection. Although CTL responses to a few persistent epitopes developed over the first two months of infection, they proliferated slowly. As CTL epitopes were replaced by mutational variants, the corresponding responses immediately declined, most rapidly in the cases of strongly selected epitopes. CTL recognition of epitope variants, via cross-reactivity and de novo responses, was common throughout the period of study. Our data demonstrate that HIV-specific CTL responses, especially in the critical acute/early stage, were focused on regions that are prone to escape. Failure of CTL responses to strongly target functional or structurally critical regions of the virus, as well as the sequential cascade of CTL responses, followed closely by viral escape and decline of the corresponding responses, likely contribute to a lack of sustainable viral suppression. Focusing early and rapidly proliferating CTL on persistent epitopes may be essential for durable viral control in HIV-1 infection.
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