Effects of genetic polymorphism in the MHC, KIR, and related loci on human disea

某些免疫反应基因的广泛变异是导致几乎所有人类疾病风险变异的宿主遗传决定因素的核心。我们已经研究了高度多态性的KIR和HLA位点，以及其他相关的、较少多态性的位点对几种疾病的遗传影响。我们对这些效应的一般理解的贡献总结在这里。NK细胞受体KIR3DL1的同种异体在与靶细胞上存在的HLA-B Bw4配体结合时，NK细胞的表达模式和抑制能力都有所不同。使用超过1500个HIV+个体的样本，我们发现KIR3DL1和HLA-B位点的多个不同等位基因组合以一致的方式显著且强烈地影响艾滋病的进展和血浆HIV RNA水平。抑制性KIR3DL1等位基因根据不同的功能特征进行分组。先前的数据表明，在具有强抑制和弱抑制的等位基因之间存在功能上的区别。总体而言，强抑制性KIR3DL1等位基因+ Bw4-80I基序的HLA-B等位基因具有较强的保护作用，弱抑制性KIR3DL1等位基因+ Bw4-80T基序的HLA-B等位基因具有较弱的保护作用。当检测单个HLA-B*57 （Bw4-80I）和HLA-B*27 （Bw4-80T）等位基因时，这些数据得到了平行结论的支持，结果表明，在存在强抑制性KIR3DL1等位基因和弱抑制性KIR3DL1等位基因时，HLA-B*57 （Bw4-80I）和HLA-B*27 （Bw4-80T）等位基因时，这些等位基因的保护作用最强。对一组901人的平均病毒载量数据的分析显示，各种KIR3DL1/HLA-B基因型的保护作用与疾病进展分析中观察到的结果显著一致。因此，这些基因型对病程的影响发生在感染后的早期，并可能持续到感染的整个慢性阶段。本研究中显示的各种KIR3DL1/Bw4基因型组合对艾滋病进展的保护作用首次支持了不同KIR3DL1异型功能对任何类型疾病结果的相应影响，并表明NK细胞在HIV感染的自然史中起着关键作用。由于HLA-B等位基因影响HIV-1疾病进展和病毒水平，我们假设它们也可能影响HIV-1传播。为了研究hiv -1感染男性中携带Bw4表位的HLA-B等位基因是否会降低向女性性伴侣传播的风险，我们研究了304名hiv -1感染血友病的男性和325名女性性伴侣。在325名妇女中，44名（13.5%）感染了艾滋病毒-1。这些女性的HIV-1感染与其男性伴侣的HLA-B基因型有关。与Bw6纯合子的男性相比，携带Bw4的男性将HIV-1传播给其女性伴侣的可能性约为一半（OR, 0.52; 95% CI, 0.27-0.98; P = 0.04）。我们得出结论，在HIV-1感染的男性中存在HLA-Bw4与男性向女性传播HIV-1的风险降低有关，这表明这些等位基因降低了HIV-1的传染性。我们还提供了基因分型数据，用于检测HLA I类多态性对HIV耐药性的功能意义的研究。我们已经开始协同努力，支持合作者描述HLA I类同种异体对HIV的不同保护。其中一些研究表明，在感染的早期阶段，强烈的先天和获得性免疫反应对于在慢性期维持对HIV的控制尤为重要。KIR3DS1是一种高度多态性基因，迄今已发现40多个等位基因，其中包括其激活对应基因KIR3DS1。我们之前的研究表明，在具有编码80位异亮氨酸的HLA B Bw4的个体中，KIR3DS1与艾滋病的缓慢进展有关。然而，由于缺乏KIR3DS1特异性抗体，其表达和功能从未被报道过。与LEI的另一组合作，我们现在使用单克隆抗体Z27（也识别KIR3DL1）证明了KIR3DS1在大量外周NK细胞上的表达。通过对KIR3DS1转染物的分析，以及鉴定出一个过早截断且不在细胞表面表达的新型KIR3DS1等位基因，证实了这种检测方法的保真度。此外，通过CD107a的表达评估，Z27连接KIR3DS1可导致NK细胞产生干扰素γ和脱颗粒。KIR3DS1的高频率表达及其激活NK细胞的能力开始解决流行病学数据，表明该受体在HIV发病机制中起关键作用。我们还参与了旨在确定KIR3DS1的配体和KIR3DS1与HLA-B Bw4相互作用中病毒肽特异性的研究。利用Sarah Rowland-Jones博士实验室建立的四聚体技术，我们已经证明KIR3DL1亚型以肽特异性的方式结合Bw4四聚体。虽然我们最初鉴定KIR3DS1配体的尝试没有成功，但我们正在继续这项工作，并取得了有希望的初步结果。急性乙型肝炎病毒（HBV）感染的恢复需要广泛而强烈的t细胞反应，当趋化因子受体5 （CCR5）缺失时，这种反应在小鼠中得到增强。为了验证无功能CCR5 （CCR5&#916；32[一种包含32-bp缺失的功能无效等位基因]）的产生增加人类从乙型肝炎中恢复的可能性的假设，该小组研究了来自三个队列的526人，其中一个HBV持久性患者与两个HBV感染后恢复的患者相匹配。对CCR5&#916；32、CCR5启动子和邻近基因编码区多态性、趋化因子受体2 （CCR2）和趋化因子受体样2 （CCRL2）进行基因分型。采用条件logistic回归方法比较190例病毒恢复患者和336例持续感染患者的等位基因和单倍型频率。CCR5&#916；32使发生持续性HBV感染的风险降低了近一半（优势比[OR]， 0.53； 95%可信区间[CI]， 0.33至0.83;P = 0.006）。这种关联在伴有和未伴有人类免疫缺陷病毒感染的人群中几乎相同。在缺失的9个纯合子个体中，8个从感染中恢复（OR, 0.25; 95% CI, 0.03 ~ 1.99; P = 0.19）。虽然之前已经发现了其他相关基因，但这种缺失很重要，因为它存在于13%的康复患者中，并且具有迄今为止公布的最强的比值比之一。检测的其他邻近多态性均与HBV预后无关。这些数据证明了CCR5&#916；32在HBV感染恢复中的保护作用，并为CCR5在HBV免疫应答中的作用提供了遗传流行病学证据。此外，这一发现支持了小鼠模型数据的事实，该数据显示，具有CCR5缺陷的t细胞对其他感染因子的反应增加，这一事实尤其令人感兴趣，因为它提供了一种潜在的方法来增强t细胞对HBV的反应。

The extensive variation at some of the immune response genes is central amongst the host genetic determinants that contribute to the variability in risk of virtually all human diseases. We have studied the genetic effects of the highly polymorphic KIR and HLA loci, as well as other related, less polymorphic loci on several diseases. Our contributions to the general understanding of these effects are summarized here. Allotypes of the NK cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their HLA-B Bw4 ligands present on target cells. Using a sample size of over 1500 HIV+ individuals, we showed that multiple distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA levels in a consistent manner. Inhibitory KIR3DL1 alleles were grouped based on distinct functional characteristics. Previous data have indicated a functional distinction between alleles that are strongly inhibitory and those that are weakly inhibitory. Overall, a pattern emerged indicating relatively strong protection through strongly inhibitory KIR3DL1 alleles + HLA-B alleles with the Bw4-80I motif and a weak protective effect through weakly inhibitory KIR3DL1 alleles + HLA-B alleles with the Bw4-80T motif. These data were reinforced by parallel conclusions when the individual HLA-B*57 (Bw4-80I) and HLA-B*27 (Bw4-80T) alleles were examined and shown to be most protective in the presence of strongly inhibitory KIR3DL1 alleles and weakly inhibitory KIR3DL1 alleles respectively. An analysis of mean viral load data determined from a group of 901 individuals, showed protective effects of the various KIR3DL1/HLA-B genotypes remarkably consistent with those observed in disease progression analyses. Thus, the influence of these genotypes on disease course occurs early after infection, and may continue throughout the chronic phase of infection. The protection against AIDS progression conferred by various combinations of KIR3DL1/Bw4 genotypes shown in this study represents the first data to support a consequential impact of differential KIR3DL1 allotypic functions on disease outcome of any sort and suggest that NK cells play a critical role in the natural history of HIV infection. Because HLA-B alleles influence HIV-1 disease progression and viral levels, we hypothesized that they might also influence HIV-1 transmission. In order to investigate if the presence of HLA-B alleles with the Bw4 epitope in HIV-1-infected men decreased the risk of transmission to their female sex partners we studied 304 HIV-1-infected men with hemophilia and 325 female sex partners. Among the 325 women, 44 (13.5%) were infected with HIV-1. HIV-1 infection in the women was associated with the HLA-B genotype of their male partner. Compared with men who were homozygous for Bw6, men who carried Bw4 were about half as likely to have transmitted HIV-1 to their female partner (OR, 0.52; 95% CI, 0.27-0.98; P = 0.04). We concluded that the presence of HLA-Bw4 in HIV-1-infected men was associated with a decreased risk of male-to-female HIV-1 transmission, which suggests that these alleles reduce infectivity for HIV-1. We have also provided genotyping data for studies in which the functional significance of HLA class I polymorphism on HIV resistance was tested. We have begun to make a concerted effort to support collaborators who are characterizing the differential protection conferred by HLA class I allotypes against HIV. Some of these studies indicate that strong innate and acquired immune responses during the early phase of infection are especially important in maintaining control over HIV during the chronic phase. KIR3DL1 is a highly polymorphic gene with more than 40 alleles described so far, including its activating counterpart, KIR3DS1. We have previously shown that KIR3DS1 associates with slow progression to AIDS in individuals who also have HLA B Bw4 encoding isoleucine at position 80. However, due to the lack of a KIR3DS1 specific antibody, expression and function have never been reported. In collaboration with another group in the LEI we have now demonstrated KIR3DS1 expression on a substantial subset of peripheral NK cells using the monoclonal antibody Z27 (which also recognizes KIR3DL1). The fidelity of this detection method was confirmed by analysis of KIR3DS1 transfectants and through the identification of a novel KIR3DS1 allele that is prematurely truncated and not expressed on the cell surface. In addition, ligation of KIR3DS1 by Z27 leads to NK cell interferon gamma production and degranulation as assessed by expression of CD107a. The high frequency of KIR3DS1 expression, together with its ability to activate NK cells begin to address the epidemiological data suggesting a critical role for this receptor in HIV pathogenesis. We have also participated in studies aimed at determining the ligand for KIR3DS1 and viral peptide specificity in the interaction between KIR3DL1 and HLA-B Bw4. Using tetramer technology established in Dr. Sarah Rowland-Jones laboratory, we have shown that KIR3DL1 subtypes bind Bw4 tetramers in a peptide-specific manner. While our original attempts to identify ligands for KIR3DS1 have been unsuccessful, we are pursuing this work with promising preliminary results. Recovery from acute hepatitis B virus (HBV) infection requires a broad, vigorous T-cell response, which is enhanced in mice when chemokine receptor 5 (CCR5) is missing. To test the hypothesis that production of a nonfunctional CCR5 (CCR5Δ32 [a functionally null allele containing a 32-bp deletion]) increases the likelihood of recovery from hepatitis B in humans, the group studied 526 persons from three cohorts in which one person with HBV persistence was matched to two persons who recovered from an HBV infection. Genotyping for CCR5Δ32 and for polymorphisms in the CCR5 promoter and in coding regions of the neighboring genes, chemokine receptor 2 (CCR2) and chemokine receptor-like 2 (CCRL2) was performed. Allele and haplotype frequencies were compared among 190 persons with viral recovery and 336 with persistent infection by use of conditional logistic regression. CCR5Δ32 reduced the risk of developing a persistent HBV infection by nearly half (odds ratio [OR], 0.53; 95% confidence interval [CI], 0.33 to 0.83; P = 0.006). This association was virtually identical in persons with and without a concomitant human immunodeficiency virus infection. Of the nine individuals who were homozygous for the deletion, eight recovered from infection (OR, 0.25; 95% CI, 0.03 to 1.99; P = 0.19). Although other relevant genes have been identified previously, this deletion is important since it is present in 13% of people who recovered and it has one of the strongest odds ratios published to date. None of the other neighboring polymorphisms examined were associated with HBV outcome. These data demonstrate a protective effect of CCR5Δ32 in recovery from an HBV infection and provide genetic epidemiological evidence for a role of CCR5 in the immune response to HBV. Further, the fact that the findings support data from mouse models showing an increased T-cell response to other infectious agents with CCR5 deficiency is particularly intriguing because it offers a potential means to enhance the T-cell response to HBV by [summary truncated at 7800 characters]