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

MHC、KIR及相关位点遗传多态性对人类疾病的影响

• 批准号: 7965675
• 负责人: Mary N. Carrington
• 金额: $ 118.76万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7965675
• 关键词: Acquired Immunodeficiency Syndrome; Activated Natural Killer Cell; Acute; Affect; Alleles; Antigen Presentation; Antiviral Agents; Autoimmune Diseases; Blood; Cell surface; Cells; Cervical; Cessation of life; Collaborations; Commit; Communicable Diseases; Containment; Couples; Cytotoxic T-Lymphocytes; Data; Development; Disease; Disease Outcome; Disease Progression; Effector Cell; Epidemiology; Epitopes; European; Female; Fetal Diseases; Genes; Genetic; Genetic Determinism; Genetic Polymorphism; Genetic Variation; Genetic screening method; Genotype; Goals; HIV; HIV Infections; HIV-1; HLA Antigens; Hand; Hepatitis C virus; Heterosexuals; Human; Immune; Immune Response Genes; Immune response; Immune system; Immunoglobulins; In Vitro; Individual; Infection; Inflammatory Bowel Diseases; Isoleucine; KIR3DS1; Killer Cells; Laboratories; Leukocytes; Ligands; Major Histocompatibility Complex; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Messenger RNA; NK cell receptor NKB1; Nasopharynx Carcinoma; Natural Killer Cells; Neoplasms; Non-Hodgkin' s Lymphoma; Nuclear Pore Complex; Other Genetics; Outcome; Phase; Plasma; Play; Population; Positioning Attribute; Pre-Eclampsia; Predisposition; Psoriatic Arthritis; RNA; Reagent; Receptor Gene; Regulation; Relative (related person); Research Personnel; Resistance; Rewards; Risk; Role; Scanning; Seminal fluid; Sexual Partners; Solid; Testing; Time; Universities; Variant; Viral; Viral Load result; Viremia; Virus; Virus Diseases; Work; base; cohort; dimorphism; genetic variant; genome-wide; human disease; human leukocyte antigen gene; killer immunoglobulin-like receptor; killings; male; melanoma; men; novel; receptor; response; therapeutic vaccine; transmission process; vector

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. Variation at the HLA class I locus has a stronger influence on HIV-1 disease outcome than that of any other genetic locus identified to date. HLA class I molecules have two fundamental roles in determining the strength of the immune response against HIV: 1) regulation of the acquired response through presentation of antigenic epitopes to cytotoxic T lymphocytes (CTL), and 2) modulation of the innate response by serving as ligands for the killer cell immunoglobulin-like receptors (KIR) expressed on natural killer (NK) cells. In both regards, HLA-B has been the primary focus relative to HLA-A and C because the strongest genetic and functional associations with HIV disease outcomes have involved this locus. Recently, however, a scan for genetic variants that influence control of viral load indicated that a dimorphism 35kb upstream of the HLA-C gene (-35C/T) had one of the two strongest genome-wide effects on the level of HIV plasma viremia in early, established HIV infection. Notably, the -35C variant that associates with low viral load has also been shown to associate with high HLA-C mRNA levels in a co-dominant manner amongst a group of individuals of European ancestry. These findings suggest that certain HLA-C allotypes may have a primary role in restricting HIV replication through innate and/or acquired immune mechanisms that have been previously overlooked. Using a cohort of 1698 individuals, we showed that the -35 variant associates very strongly with HIV outcomes during the early phase of infection by influencing steady- state viral load, and to a weaker extent with the very late phase of infection by influencing time to death. These temporal data implicate two at least partially distinct mechanisms of HIV restriction associated with the -35 variant. No individual HLA-C allotype appears to be clearly better than others in terms of controlling HIV through antigen presentation to CTL, unlike that which has been observed at the HLA-B locus. However, higher levels of HLA-C on target cell surfaces may generally result in more effective antigen presentation to CTL or enhance NK cell activity, thus boosting the immune system and leading to better viral control by the host. These data strongly implicate high HLA-C expression levels in more effective control of HIV-1, potentially through better antigen presentation to cytotoxic T lymphocytes or recognition and killing of infected cells by natural killer cells. It is well established that HLA class I plays an important role in determining the rate of progression to AIDS after infection with HIV-1. It is less clear, however, how HLA diversity affects HIV transmission. We previously showed that the HLA-Bw4 and Bw6 epitopes of the HLA-B molecules are associated with risk for HIV transmission between heterosexual couples. The presence of HLA-Bw4 in HIV-1-infected men was associated with a decreased risk of male-to-female HIV-1 transmission. More recently, we further investigated the association of individual HLA-B alleles for their respective contributions to the risk of HIV-1 transmission from HIV-infected men to their female partners. We also tested for an association of HLA-B alleles present in the female partners of HIV+ carriers on risk of becoming infected. Among the HIV-infected men, three HLA-B alleles showed a significant association with infectivity. Men positive for HLA-B*35Px (B*3502, B*3503, and B*5301), a group of alleles previously associated with rapid AIDS progression, showed an increased risk of transmitting the virus to their female partners, whereas men positive for B*27 or B*57, alleles which is associated with slow AIDS progression, transmitted the virus to their partners less frequently. On the other hand, HLA polymorphisms among female sex partners did not affect their susceptibility to HIV infection. In summary, class I HLA polymorphism appears to affect HIV-1 infectivity but not susceptibility. The HLA alleles B*35Px, B*27 and B*57 may influence both HIV-1 transmission and post-infection risk of AIDS through control of HIV-1 RNA levels in semen and blood. NK cells are critical in the early containment of viral infections. Epidemiological and functional studies have shown an important role of NK cells expressing specific killer immunoglobulin-like receptors (KIRs) in the control of HIV-1 infection, but little is known about the mechanisms that determine the expansion of these antiviral NK cell populations during acute HIV-1 infection. One particular activating KIR (KIR3DS1), in combination with its putative ligand, an HLA-B allele with isoleucine at position 80 (HLA-B Bw480I), has been previously shown by us to be associated with slower HIV-1 disease progression. They have also shown that KIR3DS1+ NK cells can effectively suppress HIV-1 replication in HLA-B Bw480I+ target cells in vitro. Furthermore, a subset of inhibitory alleles from the same locus, KIR3DL1, that show high cell surface expression levels have similarly been associated with slower disease progression toward AIDS in the presence of their ligand, HLA-B Bw480I. However, the mechanisms underlying their protective role are not understood. In collaboration with investigators at Harvard University, we assessed clonal NK cell expansions during acute HIV-1 infection by quantitative PCR and flow cytometric analysis. The results indicate that NK cells expressing the activating receptor KIR3DS1 and, to a lesser extent, the inhibitory receptor KIR3DL1 specifically expand in acute HIV-1 infection in the presence of HLA-B Bw480I, the putative HLA class I ligand for KIR3DL1/3DS1. The early accumulation of highly activated NK cells may provide a potent first-line defense allowing for the initial control of acute HIV-1 replication while adaptive immune responses are still developing. These data demonstrate for the first time the impact of the HLA class I ligands on clonal NK cell expansions during an acute human viral infection.

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。HLA I类位点的变异对HIV-1疾病结果的影响比迄今为止发现的任何其他基因位点都要大。HLA I类分子在决定抗HIV免疫反应的强度方面有两个基本作用：1)通过向细胞毒性T淋巴细胞（CTL）呈递抗原表位来调节获得性反应；2)通过作为自然杀伤细胞（NK）上表达的杀伤细胞免疫球蛋白样受体（KIR）的配体来调节先天反应。在这两个方面，相对于HLA-A和C， HLA-B一直是主要的焦点，因为与HIV疾病结果最强的遗传和功能关联涉及该位点。然而，最近对影响病毒载量控制的遗传变异的扫描表明，在早期确定的HIV感染中，HLA-C基因上游35kb的二态性（-35C/T）对HIV血浆病毒血症水平具有两个最强的全基因组影响之一。值得注意的是，与低病毒载量相关的-35C变异也被证明与高HLA-C mRNA水平在欧洲血统个体群体中以共显性方式相关。这些发现表明，某些HLA-C同种异体可能通过先天和/或获得性免疫机制在限制HIV复制中起主要作用，这在以前被忽视。通过对1698个个体的队列研究，我们发现-35变异在感染早期通过影响稳态病毒载量与HIV结果密切相关，而在感染晚期通过影响死亡时间与HIV结果的关联程度较弱。这些时间数据暗示了与-35变异相关的两种至少部分不同的HIV限制机制。与在HLA-B位点观察到的情况不同，在通过向CTL呈递抗原来控制HIV方面，没有单个HLA-C异型明显优于其他异型。然而，靶细胞表面较高水平的HLA-C通常会导致更有效的抗原向CTL呈递或增强NK细胞活性，从而增强免疫系统并导致宿主更好地控制病毒。这些数据强烈暗示，高HLA-C表达水平可以更有效地控制HIV-1，可能通过更好的抗原向细胞毒性T淋巴细胞呈递或自然杀伤细胞识别和杀死感染细胞。已经确定HLA I类在决定HIV-1感染后艾滋病进展率方面起着重要作用。然而，HLA多样性如何影响HIV传播尚不清楚。我们之前的研究表明，HLA-B分子的HLA-Bw4和Bw6表位与异性伴侣之间HIV传播的风险相关。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。最近，我们进一步研究了单个HLA-B等位基因对HIV-1从hiv感染的男性传播给其女性伴侣的风险的影响。我们还检测了HIV阳性携带者的女性伴侣中存在的HLA-B等位基因与感染风险的关联。在艾滋病毒感染的男性中，三个HLA-B等位基因显示出与传染性显著相关。HLA-B*35Px (B*3502、B*3503和B*5301)（一组先前与艾滋病快速进展相关的等位基因）阳性的男性将病毒传播给其女性伴侣的风险增加，而B*27或B*57（与艾滋病缓慢进展相关的等位基因）阳性的男性将病毒传播给其伴侣的频率较低。另一方面，女性性伴侣的HLA多态性不影响其对HIV感染的易感性。总之，I类HLA多态性似乎影响HIV-1的感染性，但不影响易感性。HLA等位基因B*35Px、B*27和B*57可能通过控制精液和血液中HIV-1 RNA水平影响HIV-1传播和艾滋病感染后风险。NK细胞对病毒感染的早期控制至关重要。流行病学和功能研究表明，表达特异性杀伤免疫球蛋白样受体（KIRs）的NK细胞在控制HIV-1感染中发挥重要作用，但在急性HIV-1感染期间，决定这些抗病毒NK细胞群扩增的机制知之甚少。一种特殊的激活KIR (KIR3DS1)，结合其假定的配体，在80位具有异亮氨酸的HLA-B等位基因（HLA-B Bw480I），先前已被我们证明与减缓HIV-1疾病进展有关。他们还表明，KIR3DS1+ NK细胞可以在体外有效抑制HLA-B Bw480I+靶细胞中的HIV-1复制。此外，来自同一基因座的一组抑制性等位基因KIR3DL1，在其配体HLA-B Bw480I存在的情况下，显示出高细胞表面表达水平，同样与艾滋病疾病进展缓慢相关。然而，其保护作用的机制尚不清楚。与哈佛大学的研究人员合作，我们通过定量PCR和流式细胞术分析评估了急性HIV-1感染期间克隆NK细胞的扩增情况。结果表明，NK细胞表达激活受体KIR3DS1和抑制受体KIR3DL1，在较小程度上，特异性扩增在急性HIV-1感染存在HLA- b Bw480I，假定的HLA I类配体KIR3DL1/ 3ds1。高度活化的NK细胞的早期积累可能提供有效的一线防御，允许在适应性免疫反应仍在发展时对急性HIV-1复制进行初始控制。这些数据首次证明了HLA I类配体在急性人类病毒感染期间对克隆NK细胞扩增的影响。