Evidence of differential HLA class I-mediated viral evolution in functional and accessory/regulatory genes of HIV-1.
Evidence of differential HLA class I-mediated viral evolution in functional and accessory/regulatory genes of HIV-1.
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DOI：
10.1371/journal.ppat.0030094
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发表时间：
2007-07
期刊：
影响因子：
6.7
通讯作者：
Harrigan PR
中科院分区：
文献类型：
--
作者：
Brumme ZL;Brumme CJ;Heckerman D;Korber BT;Daniels M;Carlson J;Kadie C;Bhattacharya T;Chui C;Szinger J;Mo T;Hogg RS;Montaner JS;Frahm N;Brander C;Walker BD;Harrigan PR
尽管 HIV-1 具有强大的突变能力和序列多样性，但有证据表明，响应特定选择压力的病毒进化遵循通常可预测的突变途径。对临床衍生的 HIV 序列进行基于群体的分析可用于识别病毒基因中的免疫逃逸突变；然而，由于无法区分主动免疫选择和病毒创建者效应，先前识别此类突变的尝试变得复杂。此外，体内免疫选择下产生的突变与 HIV-1 等高度变异病原体的疾病进展之间的关联仍不完全清楚。我们应用病毒谱系校正分析方法来研究一大群慢性感染、未接受过抗逆转录病毒治疗的个体中 HIV 蛋白酶、逆转录酶 (RT)、Vpr 和 Nef 中 HLA I 类相关序列印记。总共观察到了 478 个独特的 HLA 相关多态性，并将其组织成一系列“逃逸图”，这些图在体内选择压力下识别已知和推定的细胞毒性 T 淋巴细胞 (CTL) 表位。我们的数据表明，免疫逃逸途径是可以根据宿主 HLA I 类谱预测的，并且表位锚定残基不是 CTL 逃逸的首选位点。结果揭示了免疫印记对病毒基因多样性的不同贡献，与其他基因相比，Nef 表现出更多的 HLA I 类介导选择的证据。此外，这些数据揭示了 HLA 相关多态性与通过 CD4+ T 细胞计数估计的 HIV 疾病阶段之间存在显着的、剂量依赖性的负相关。 HIV 蛋白酶、RT、Vpr 和 Nef 中 HLA 相关多态性的特定位点和模式的鉴定阐明了在体内主动免疫选择压力下编码这些产物的基因区域。与研究的其他基因相比，Nef 中 HLA 相关多态性的高密度表明不同病毒基因中 HLA I 类驱动的进化存在差异。 HLA I 类相关多态性与较低 CD4+ 细胞计数之间的关系表明，免疫逃逸与疾病状态相关，支持维持有效 CTL 反应在 HIV-1 免疫控制中的重要作用。基于 CTL 的预防性和治疗性疫苗方法的设计可以纳入有关可预测逃逸途径的信息。当今 HIV-1 疫苗设计面临的最大挑战之一是病毒具有强大的突变和适应能力，这一特性导致了当今观察到的 HIV-1 毒株在全球范围内存在广泛的遗传变异。在个体基础上，每个感染者独特的免疫反应施加的进化选择压力导致能够逃避免疫识别的病毒“逃逸”突变体的选择和产生，而在群体基础上，人类免疫系统的高度多态性基因施加的复杂进化选择压力在全球范围内塑造了HIV-1多样性。理解艾滋病毒免疫逃逸看似无限的复杂性对于我们开发成功的艾滋病毒疫苗的目标至关重要。目前的研究使用尖端的统计方法来识别各种 HIV 基因中人类白细胞抗原 (HLA) I 类限制性逃逸突变的特定位点和模式。研究人员以“免疫逃逸图”的形式总结了他们的发现，强调了免疫印记对艾滋病毒遗传多样性的不同贡献，并确定了主动免疫选择压力下病毒基因组中的特定位点。本研究的结果有助于我们了解人类免疫选择压力如何导致不同艾滋病毒基因的变异，并有助于为考虑病毒多样性的艾滋病毒疫苗的开发提供信息。
Despite the formidable mutational capacity and sequence diversity of HIV-1, evidence suggests that viral evolution in response to specific selective pressures follows generally predictable mutational pathways. Population-based analyses of clinically derived HIV sequences may be used to identify immune escape mutations in viral genes; however, prior attempts to identify such mutations have been complicated by the inability to discriminate active immune selection from virus founder effects. Furthermore, the association between mutations arising under in vivo immune selection and disease progression for highly variable pathogens such as HIV-1 remains incompletely understood. We applied a viral lineage-corrected analytical method to investigate HLA class I-associated sequence imprinting in HIV protease, reverse transcriptase (RT), Vpr, and Nef in a large cohort of chronically infected, antiretrovirally naïve individuals. A total of 478 unique HLA-associated polymorphisms were observed and organized into a series of “escape maps,” which identify known and putative cytotoxic T lymphocyte (CTL) epitopes under selection pressure in vivo. Our data indicate that pathways to immune escape are predictable based on host HLA class I profile, and that epitope anchor residues are not the preferred sites of CTL escape. Results reveal differential contributions of immune imprinting to viral gene diversity, with Nef exhibiting far greater evidence for HLA class I-mediated selection compared to other genes. Moreover, these data reveal a significant, dose-dependent inverse correlation between HLA-associated polymorphisms and HIV disease stage as estimated by CD4+ T cell count. Identification of specific sites and patterns of HLA-associated polymorphisms across HIV protease, RT, Vpr, and Nef illuminates regions of the genes encoding these products under active immune selection pressure in vivo. The high density of HLA-associated polymorphisms in Nef compared to other genes investigated indicates differential HLA class I-driven evolution in different viral genes. The relationship between HLA class I-associated polymorphisms and lower CD4+ cell count suggests that immune escape correlates with disease status, supporting an essential role of maintenance of effective CTL responses in immune control of HIV-1. The design of preventative and therapeutic CTL-based vaccine approaches could incorporate information on predictable escape pathways. One of the greatest challenges facing HIV-1 vaccine design today is the formidable capacity of the virus for mutation and adaptation, a characteristic that has contributed to the extensive worldwide genetic variability of HIV-1 strains observed today. On an individual basis, evolutionary selective pressures imposed by each infected person's unique immune response results in the selection and outgrowth of viral “escape” mutants capable of evading immune recognition, while on a population basis, complex evolutionary selective pressures imposed by the highly polymorphic genes of the human immune system shape HIV-1 diversity on a global level. Making sense of the seemingly infinite complexity of HIV immune escape is of paramount importance in our goal of developing a successful HIV vaccine. The current study uses cutting-edge statistical methods to identify specific sites and patterns of human leukocyte antigen (HLA) class I-restricted escape mutations in various HIV genes. Researchers summarize their findings in the form of “immune escape maps,” which highlight the differential contribution of immune imprinting to HIV genetic diversity, as well as identify specific sites in the viral genome under active immune selection pressure. Results from the present study contribute to our understanding of how human immune selective pressure contributes to variation in different HIV genes, and could help inform the development of HIV vaccines that take into consideration viral diversity.
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影响因子：
64.8
作者：
Goulder, PJR;Brander, C;Walker, BD
通讯作者：
Walker, BD
影响因子：
82.9
作者：
KOENIG, S;CONLEY, AJ;LANE, HC
通讯作者：
LANE, HC
影响因子：
5.4
作者：
Casazza, JP;Betts, MR;Koup, RA
通讯作者：
Koup, RA
DOI：
10.1084/jem.20052116
发表时间：
2006-03-20
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Draenert R;Allen TM;Liu Y;Wrin T;Chappey C;Verrill CL;Sirera G;Eldridge RL;Lahaie MP;Ruiz L;Clotet B;Petropoulos CJ;Walker BD;Martinez-Picado J
通讯作者：
Martinez-Picado J
影响因子：
82.9
作者：
Goulder, PJR;Phillips, RE;RowlandJones, S
通讯作者：
RowlandJones, S