Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa.
Selection of an HLA-C*03:04-Restricted HIV-1 p24 Gag Sequence Variant Is Associated with Viral Escape from KIR2DL3+ Natural Killer Cells: Data from an Observational Cohort in South Africa.
复制标题
DOI：
10.1371/journal.pmed.1001900
复制
发表时间：
2015-11
期刊：
影响因子：
15.8
通讯作者：
Altfeld M
中科院分区：
文献类型：
--
作者：
Hölzemer A;Thobakgale CF;Jimenez Cruz CA;Garcia-Beltran WF;Carlson JM;van Teijlingen NH;Mann JK;Jaggernath M;Kang SG;Körner C;Chung AW;Schafer JL;Evans DT;Alter G;Walker BD;Goulder PJ;Carrington M;Hartmann P;Pertel T;Zhou R;Ndung'u T;Altfeld M
病毒可以逃避免疫监视，但其潜在机制尚不清楚。在这里，我们试图了解自然杀伤（NK）细胞识别hiv -1感染细胞的机制，以及这种病毒如何逃避NK细胞介导的免疫压力。在南非的HIV-1进化枝C病毒（n = 392）中发现了两个与特异性KIR/HLA组合基因型存在相关的p24 Gag序列突变，这表明病毒通过HLA i类表位内的序列变异从KIR+ NK细胞中逃逸。在KIR2DL3和HLA-C*03:04感染的个体中，p24 Gag (TGag303V) 303位的一个序列多态性使抑制KIR2DL3受体与表达该变异表位的HLA-C*03:04细胞的结合明显优于野生型表位（野生型平均18.01±10.45标准差[SD]，变异平均44.67±14.42标准差，p = 0.002）。此外，与呈现野生型序列的细胞相比，健康供体的KIR2DL3+ NK细胞对HLA-C*03:04+靶细胞的激活显著降低（野生型平均标准误差为0.78±0.07，变异平均值为0.63±0.07,p = 0.012）。在不同病毒序列变异的背景下，KIR/肽/HLA相互作用的结构建模和表面等离子体共振支持了这些结果。未来的研究将需要评估所调查的HIV-1表位在自然感染中的加工和抗原呈递，以及对病毒控制的影响。这些数据为病毒如何通过选择hla呈递表位的突变来逃避NK细胞免疫提供了新的见解，这些突变增强了与抑制性NK细胞受体的结合。更好地了解HIV-1逃避NK细胞介导的免疫压力的机制和结构建模方法的功能验证将有助于开发新的靶向免疫干预措施来利用NK细胞的抗病毒活性。来自南非的一项队列分析揭示了HIV病毒如何通过获得hla介导的表位突变来逃避NK细胞免疫，这影响了与NK细胞受体的结合。在我们的一生中，我们的免疫系统——一个由细胞、组织和器官组成的复杂网络——保护我们免受病毒、细菌、寄生虫和真菌的攻击。人体抵御这些“病原体”的第一道防线是先天免疫系统，它是一组细胞和蛋白质的集合，随时准备识别并杀死各种各样的外来入侵者。除了直接杀死病原体外，先天免疫系统还激活适应性免疫反应，识别和杀死特定的病原体，并负责免疫记忆。大多数病原体都能被免疫系统的两臂快速有效地清除，但一些传染性病原体已经找到了逃避免疫反应的方法。例如，感染导致艾滋病的HIV-1病毒，即使人体产生强烈的HIV-1特异性免疫反应，也会导致病毒长时间持续复制。在很大程度上，HIV-1逃避免疫反应反映了它杀死病毒特异性CD4淋巴细胞的能力，而CD4淋巴细胞是帮助其他免疫系统细胞杀死HIV-1感染细胞所需要的。此外，HIV-1表面被人类免疫系统识别的蛋白质（病毒抗原）经常发生变化（突变），这使得免疫系统更难从人体中清除HIV-1。病毒以多种方式逃避免疫监视，如果我们更好地了解免疫逃避的机制，就有可能开发出有针对性的免疫干预措施来对付HIV-1等病毒。在这里，研究人员研究了自然杀伤（NK）细胞（一种淋巴细胞，是先天抗病毒免疫反应的重要组成部分）如何识别hiv感染的细胞以及HIV-1如何逃避NK细胞介导的免疫压力。NK细胞的激活是由几种不同受体家族（包括杀伤细胞免疫球蛋白样受体家族）传递给细胞的抑制和激活信号的整合决定的。kir主要与靶细胞上的人类白细胞抗原（HLA） I类分子（配体）结合。HLA I类蛋白在细胞表面显示感染细胞中病原体的片段（表位；免疫系统识别的肽），以便免疫系统知道该细胞需要被破坏。不同的KIRs与HLA I类配体的结合取决于HLA I类分子的序列和HLA I类分子所呈现的表位的序列。因此，研究人员假设HIV-1可能通过在HLA I类分子呈递的表位内获得突变来逃避NK细胞介导的免疫监视，这些突变增强了抑制性KIRs对NK细胞的作用，从而抑制NK细胞的活性。为了研究这个模型，研究人员询问在HIV-1感染的个体中，编码p24 Gag蛋白的HIV-1基因的多态性（自然发生的遗传变异）是否在群体水平上被选择，表达KIRs和HLA I类配体的特定组合。利用统计学方法鉴定了来自南非的大量未经治疗的hiv -1感染者的KIR/HLA联合基因型，他们发现在同时表达HLA- c *03:04和KIR2DL3的个体中选择了p24 Gag的特定序列多态性。功能研究表明，这种变异HIV-1表位的选择导致KIR2DL3（一种抑制性KIR）与HLA-C*03:04的结合比野生型表位更好。此外，来自健康供体的kir2dl3阳性NK细胞在HLA-C*03:04阳性靶细胞呈递变异表位时的活化程度明显低于kir2dl3阳性NK细胞在呈递野生型表位的靶细胞时的活化程度。需要进一步的研究来评估这种和其他病毒序列变异对病毒适应性的影响，在自然感染期间突变表位的加工和呈现，以及患者体内HIV-1复制的控制。然而，这些发现为HIV-1（以及可能具有高突变率的其他病毒）如何通过选择HLA呈递表位中的突变来逃避NK细胞免疫提供了新的见解，这些突变可以增强抑制性KIRs与HLA I类/肽复合物的结合。更好地了解这种逃避免疫监视的分子机制应该有助于开发靶向免疫干预措施（例如，使用kir阻断抗体，其中一些已经在临床试验中用于治疗癌症），以最大限度地发挥NK细胞的抗病毒活性。这个资源列表包含可以在设备上查看PDF时访问的链接，也可以通过http://dx.doi.org/10.1371/journal.pmed.1001900上文章的在线版本访问这些链接。美国国家过敏和传染病研究所提供了人体免疫系统的简单描述，并提供了有关艾滋病毒感染和艾滋病各方面的信息。国际艾滋病慈善机构Avert提供了有关艾滋病毒/艾滋病许多方面的信息；Avert也提供关于HIV/AIDS患者的个人故事。英国免疫学学会提供关于免疫学各个方面的短文，包括关于宿主-病原体相互作用和免疫逃避的一般信息，以及关于HIV和免疫逃避的具体信息。维基百科有关于自然杀伤细胞、kir和HLA分子的页面（注意，维基百科是一个免费的在线百科全书，任何人都可以编辑；有几种语言版本）。
Viruses can evade immune surveillance, but the underlying mechanisms are insufficiently understood. Here, we sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK-cell-mediated immune pressure. Two sequence mutations in p24 Gag associated with the presence of specific KIR/HLA combined genotypes were identified in HIV-1 clade C viruses from a large cohort of infected, untreated individuals in South Africa (n = 392), suggesting viral escape from KIR+ NK cells through sequence variations within HLA class I—presented epitopes. One sequence polymorphism at position 303 of p24 Gag (TGag303V), selected for in infected individuals with both KIR2DL3 and HLA-C*03:04, enabled significantly better binding of the inhibitory KIR2DL3 receptor to HLA-C*03:04-expressing cells presenting this variant epitope compared to the wild-type epitope (wild-type mean 18.01 ± 10.45 standard deviation [SD] and variant mean 44.67 ± 14.42 SD, p = 0.002). Furthermore, activation of primary KIR2DL3+ NK cells from healthy donors in response to HLA-C*03:04+ target cells presenting the variant epitope was significantly reduced in comparison to cells presenting the wild-type sequence (wild-type mean 0.78 ± 0.07 standard error of the mean [SEM] and variant mean 0.63 ± 0.07 SEM, p = 0.012). Structural modeling and surface plasmon resonance of KIR/peptide/HLA interactions in the context of the different viral sequence variants studied supported these results. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control. These data provide novel insights into how viruses can evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance binding to inhibitory NK cell receptors. Better understanding of the mechanisms by which HIV-1 evades NK-cell-mediated immune pressure and the functional validation of a structural modeling approach will facilitate the development of novel targeted immune interventions to harness the antiviral activities of NK cells. An analysis from a cohort in South Africa reveals how the HIV virus may escape NK cell immunity by acquiring mutations in HLA-mediated epitopes, which affect binding to NK cell receptors. Throughout life, our immune system—a complex network of cells, tissues, and organs—protects us from attack by viruses, bacteria, parasites, and fungi. The body’s first line of defense against these “pathogens” is the innate immune system, a collection of cells and proteins that is always ready to identify and kill a wide range of foreign invaders. As well as directly killing pathogens, the innate immune system activates the adaptive immune response, which recognizes and kills specific pathogens and is responsible for immunological memory. Most pathogens are dispatched quickly and effectively by the two arms of the immune system, but some infectious agents have found ways to evade the immune response. For example, infection with HIV-1, the virus that causes AIDS, results in prolonged, continuous viral replication even though the human body mounts a vigorous HIV-1-specific immune response. In large part, HIV-1’s evasion of the immune response reflects its ability to kill virus-specific CD4 lymphocytes, which are needed to help other immune system cells kill HIV-1-infected cells. In addition, the proteins on the surface of HIV-1 that are recognized by the human immune system (viral antigens) frequently acquire changes (mutations) that make it harder for the immune system to clear HIV-1 from the human body. Viruses evade immune surveillance in many ways, and if we understood the mechanisms underlying immune evasion better, it might be possible to develop targeted immune interventions to deal with viruses such as HIV-1. Here, the researchers investigate how natural killer (NK) cells, a type of lymphocyte that is an important component of the innate antiviral immune response, recognize HIV-infected cells and how HIV-1 evades NK-cell-mediated immune pressure. NK cell activation is determined by the integration of inhibitory and activating signals delivered to the cells by several different receptor families, including the family of killer-cell immunoglobulin-like receptors (KIRs). KIRs mainly bind to human leukocyte antigen (HLA) class I molecules (ligands) on their target cells. HLA class I proteins display fragments (epitopes; peptides recognized by the immune system) of pathogens present in infected cells on the cell surface so that the immune system knows that that cell needs destroying. The binding of distinct KIRs to HLA class I ligands depends on both the sequence of the HLA class I molecule and the sequence of the epitope presented by that HLA class I molecule. Thus, the researchers hypothesized that HIV-1 might evade NK-cell-mediated immune surveillance by acquiring mutations within epitopes presented by HLA class I molecules that enhance the engagement of inhibitory KIRs on NK cells, thereby inhibiting NK cell activity. To investigate this model, the researchers asked whether any polymorphisms (naturally occurring genetic variations) in the HIV-1 gene encoding the p24 Gag protein were selected on a population level in HIV-1-infected individuals expressing specific combinations of KIRs and HLA class I ligands. Using statistical methods to identify KIR/HLA combined genotypes in a large group of untreated HIV-1-infected individuals from South Africa, they showed that a specific sequence polymorphism in p24 Gag was selected for in individuals expressing both HLA-C*03:04 and KIR2DL3. Functional studies showed that the selection of this variant HIV-1 epitope resulted in better binding of KIR2DL3, an inhibitory KIR, to HLA-C*03:04 than the wild-type epitope. Moreover, the activation of KIR2DL3-positive NK cells from healthy donors in response to HLA-C*03:04-positive target cells presenting the variant epitope was significantly reduced compared to the activation of KIR2DL3-positive NK cells in response to target cells presenting the wild-type epitope. Further studies are needed to assess the consequences of this and other viral sequence variants for viral fitness, the processing and presentation of the mutant epitope during natural infections, and the control of HIV-1 replication in patients. However, these findings provide new insights into how HIV-1 (and possibly other viruses that have a high mutation rate) might evade NK cell immunity through the selection of mutations in HLA-presented epitopes that enhance the binding of inhibitory KIRs to HLA class I/peptide complexes. A better understanding of this molecular mechanism for evasion of immune surveillance should facilitate the development of targeted immune interventions (for example, the use of KIR-blocking antibodies, some of which are already being clinically tested for the treatment of cancer) to maximize the antiviral activities of NK cells. This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001900. The US National Institute of Allergy and Infectious Diseases provides a simple description of the human immune system and information on all aspects of HIV infection and AIDS Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS; Avert also provides personal stories about living with HIV/AIDS The British Society for Immunology provides short articles about various aspects of immunology, including general information about host–pathogen interactions and immune evasion and specific information about HIV and immune evasion Wikipedia has pages on natural killer cells, KIRs, and HLA molecules (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)