CHARACTERIZATION OF VARIATION IN THE CCR5 GENE

CCR5 基因变异的特征

• 批准号: 6101059
• 负责人: M N CARRINGTON
• 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/6101059
• 关键词: cytokine receptors; gene frequency; human genetic material tag; human immunodeficiency virus 1; human population genetics; immunogenetics; racial /ethnic difference; virus infection mechanism; virus receptors

The CCR5 gene encodes a molecule which serves as a secondary receptor on macrophages and CD4+ T cells for certain strains of HIV-1. We and others have previously identified a mutant of CCR5 characterized by a 32 base pair deletion, which protects from infection in homozygotes and prolongs time to AIDS in infected heterozygotes. We have continued to type cohorts for this mutation with a total number of 672 HIV- and 1,935 HIV+ individuals. While the genotype frequencies of homozygous wild- type, as well as the heterozygous wild-type/deletion, is equivalent in the HIV-1- and HIV-1+ samples, homozygotes for CCR5delta32 are significantly more frequent in HIV-1- than HIV-1+ individuals (p=0.00000000007). We have also identified 16 additional variants in the coding region of the CCR5 gene, all 3 of which are codon coding altering. The high predominance of codon- altering alleles among CCR5 mutants is consistent with an adaptive accumulation of function-altering alleles for this gene, perhaps as a consequence of historic selective pressures. We have identified two HIV-1+ individuals who are homozygous for the CCR5delta32 mutation, providing evidence that although homozygosity for this mutation provides strong resistance to HIV-1 infection, it does not afford complete protection. Preliminary analysis has suggested that these individuals became infected with HIV-1 isolates which use the CXCR4 molecule, rather than CCR5, as a coreceptor for infection. A genotype survey of 4,008 individuals revealed a cline in the CCR5delta32 frequencies from north to south in Europe. The variant was missing in native Africans, native Americans, and East Asian ethnic groups. The data indicate that the mutation occurred once in an ancestral Caucasian population.

CCR 5基因编码一种作为次级受体的分子 对巨噬细胞和CD 4 + T细胞的影响。我们和 其他人先前已经鉴定了CCR 5的突变体，其特征在于： 32个碱基对缺失，这可以保护纯合子免受感染， 杂合子感染者到艾滋病的时间为10年。我们继续 型队列的这种突变，总数为672艾滋病毒-和1935 艾滋病毒阳性者。而野生型纯合子的基因型频率 型，以及杂合野生型/缺失，在 HIV-1-和HIV-1+样品，CCR 5 δ 32的纯合子， 在HIV-1-个体中的发生率显著高于HIV-1+个体 （p= 0.0000000007）。我们还确定了16个额外的变体， CCR 5基因的编码区，所有3个都是密码子编码区 改变CCR 5中密码子改变等位基因的高优势 突变体与功能改变的适应性积累一致 这个基因的等位基因，也许是历史选择性的结果， 压力 我们已经确定了两个HIV-1+个体，他们是纯合子， CCR 5delta 32突变，提供了证据表明，虽然纯合性， 这种突变提供了对HIV-1感染的强大抵抗力，它不 提供全面保护。初步分析表明， 这些人感染了HIV-1分离株， CXCR 4分子，而不是CCR 5，作为感染的辅助受体。 一项对4,008名个体的基因型调查显示， CCR 5delta 32频率在欧洲从北到南。该变体是 在非洲土著人、美洲土著人和东亚族裔中失踪的人 组数据表明，突变发生在一个 祖先高加索人