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: 2463669
• 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/2463669
• 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 (CKR5delta32) 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 (+/delta32) 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 CKR5delta32 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，都有一些人 不同的人群对传染源的反应不同。 虽然 对感染的抗性是最常见的可变表型， 还观察到疾病结果的变化。 流行病学 研究表明，遗传因素与 传染源的死亡率。 HIV-1流行病是一个严重的 将现有遗传技术应用于宿主研究的挑战 感染和感染易感性的遗传变异。 这 HIV-1研究中的问题因HIV-1的快速传播而变得混乱 病毒的进化。 CKR 5基因作为CD 4 + T淋巴细胞上的第二受体， 人类免疫缺陷病毒的某些菌株。 CKR 5基因是 定位于人类染色体3 p21，和一个32碱基对缺失等位基因 （CKR 5 δ 32）被鉴定为以 在高加索人群中约为0.10。 1955年的考试 纳入6项特征明确的艾滋病队列研究的患者 结果显示，18个缺失纯合子仅发生在612个 暴露于HIV-1抗体阴性个体（2.8%），1343例未暴露于HIV-1抗体阴性个体（2.8%） HIV-1感染者。 CKR 5缺失杂合子（+/delta 32） 在HIV-1感染后存活的患者中， 超过10年，在某些情况下，频率是他们的两倍。 发生在艾滋病快速进展者中。 生存分析明确 显示CKR 5缺失的疾病进展较慢 杂合子 CKR 5delta 32缺失可能作为隐性遗传， 限制性基因对HIV-1感染，并发挥显性 在感染患者中延迟进展为AIDS的表型。 在 此外，我们还发现了CKR 5基因中的其他五个变异， 包括保守残基中的四个错义改变，以及一个氨基酸 酸性缺失 这些变化将进一步增加 了解CKR 5在HIV感染和疾病中的作用 进展