CHARACTERIZATION OF VARIATION IN THE CCR5 GENE

CCR5 基因变异的特征

• 批准号: 6161159
• 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/6161159
• 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.

CCR5 基因编码一种作为次级受体的分子 对某些 HIV-1 菌株的巨噬细胞和 CD4+ T 细胞的影响。我们和 其他人之前已经鉴定出 CCR5 的突变体，其特征是 32个碱基对缺失，可防止纯合子和 延长受感染杂合子感染艾滋病的时间。我们一直在继续 该突变的类型队列共有 672 名 HIV 感染者和 1,935 名 HIV 感染者 HIV+ 个体。而纯合野生型的基因型频率 类型，以及杂合野生型/缺失，在 HIV-1- 和 HIV-1+ 样本中，CCR5delta32 的纯合子是 HIV-1- 个体中的发生率明显高于 HIV-1+ 个体 （p=0.00000000007）。我们还发现了 16 个其他变体 CCR5基因的编码区，所有3个都是密码子编码 改变。 CCR5 中密码子改变等位基因的高度优势 突变体与功能改变的适应性积累一致 该基因的等位基因，也许是历史选择性的结果 压力。 我们已经确定了两名 HIV-1+ 个体，他们是纯合子 CCR5delta32 突变，提供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，但它并没有 提供完整的保护。初步分析表明 这些人感染了 HIV-1 分离株，这些分离株使用 CXCR4 分子，而不是 CCR5，作为感染的辅助受体。 对 4,008 人进行的基因型调查显示， CCR5delta32 频率在欧洲从北到南。变体是 非洲原住民、美洲原住民和东亚人种中缺失 组。数据表明突变发生在 祖先为白种人。