ROLE OF CHEMOKINES AND CHEMOKINE RECEPTORS IN AIDS

趋化因子和趋化因子受体在艾滋病中的作用

• 批准号: 6160946
• 负责人: M DEAN
• 金额: --
• 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/6160946
• 关键词: HIV infections; chemokine; clinical research; cytokine receptors; disease /disorder proneness /risk; enzyme activity; gene frequency; gene mutation; genetic mapping; genetic polymorphism; helper T lymphocyte; human genetic material tag; human immunodeficiency virus 1; human population genetics; human subject; immunogenetics; nucleic acid sequence; virus receptors

In all well-characterized epidemics there are individuals in the population that respond differently to the infectious agent. Although resistance to infection is the most common variable phenotype, variation in disease outcomes has also been observed. Epidemiologic studies have shown that inherited factors are involved in the risk of mortality to infectious agents. The HIV-1 epidemic presents a critical challenge to apply current genetic techniques to the study of host genetic variation for infection and susceptibility to infection. This problem is confounded in the studies of HIV-1 by the rapid rate of evolution of the virus. The CKR5 gene serves as a secondary receptor on CD4+ T lymphocytes for certain strains of human immunodeficiency virus. The CKR5 gene was mapped to human chromosome 3p21, and a 32 base pair deletion allele (CKR5D32) was identified that is present at a frequency of approximately 0.10 in the Caucasian population. An examination of 1955 patients included among six well-characterized AIDS cohort studies revealed that 18 deletion homozygotes occur exclusively among 612 exposed HIV-1- antibody negative individuals (2.8%) and not in 1343 HIV-1-infected individuals. CKR5 deletion heterozygotes (+/D32) were significantly elevated among patients that survive HIV-1 infection for more than 10 years, in some cases twice as frequent as their occurrence in rapid progressors to AIDS. Survival analysis clearly shows that disease progression is slower in CKR5 deletion heterozygotes. The CKR5D32 deletion may act as a recessive restriction gene against HIV-1 infection and exerts a dominant phenotype of delaying progression to AIDS among infected patients. In addition, we have identified five other alterations in the CKR5 gene, including four missense alterations in conserved residues, and an amino acid deletion. These alterations should further add to the understanding of the role of CKR5 in HIV infection and disease progression.

在所有特征明确的流行病中， 不同的人群对传染源的反应不同。虽然 抗感染是最常见的变异表型，变异 在疾病的结果也被观察到。流行病学研究 表明遗传因素与死亡风险有关， 传染源艾滋病毒-1的流行对艾滋病毒/艾滋病 应用现代遗传学技术研究寄主遗传变异 感染和感染易感性。这个问题 在HIV-1的研究中， 病毒 CKR5基因作为CD4 + T淋巴细胞上的第二受体， 人类免疫缺陷病毒的某些菌株。CKR5基因是 定位于人类染色体3p21，和一个32碱基对缺失等位基因 （CKR5D32）被鉴定为以大约 0.10在高加索人群中。对1955名患者的检查 包括在六个特征明确的艾滋病队列研究中， 18例缺失纯合子仅发生在612例HIV-1暴露者中， 抗体阴性者（2.8%），而1343名HIV-1感染者中没有 个体CKR5缺失杂合子（+/D32）与正常对照组相比， 在HIV-1感染后存活超过10年的患者中， 在某些情况下，其发生频率是快速 艾滋病的进展者。生存分析清楚地表明， 在CKR5缺失杂合子中进展较慢。CKR5D32 缺失可能作为抗HIV-1感染的隐性限制基因 并发挥了延缓艾滋病进展的显性表型， 感染的病人。此外，我们还发现了另外五名 CKR5基因的改变，包括四个错义改变， 保守残基和氨基酸缺失。这些变化应 进一步增加对CKR5在HIV感染中作用的理解 和疾病进展。