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基因编码一种作为第二受体的分子 对某些HIV-1毒株的巨噬细胞和CD4+T细胞的作用。我们和 其他人之前已经发现了CCR5的一个突变体，其特征是 32碱基对缺失，保护纯合子和 在受感染的杂合子中延长艾滋病的时间。我们一直在继续 该突变的类型队列总数为672例HIV-和1,935例 HIV+的个人。而纯合子野生型- 类型以及杂合的野生型/缺失在 在HIV-1和HIV-1+样本中，CCR5delta32的纯合子是 HIV-1-比HIV-1+患者的发病率高得多 (P=0.00000000007)。我们还发现了16个额外的变种 CCR5基因编码区，3个均为密码子编码 正在改变。CCR5密码子改变等位基因的高优势 突变与功能改变的适应性积累是一致的 这个基因的等位基因，可能是历史选择性的结果 压力。 我们已经确定了两个HIV-1+个体是纯合的 CCR5delta32突变，提供了证据，尽管 这种突变对HIV-1感染有很强的抵抗力，但它不能 提供全面的保护。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名个体进行的基因调查显示， CCR5delta32个频率在欧洲从北到南。变种是 在非洲原住民、美国原住民和东亚民族中缺失 组。数据表明，这种突变发生在一次 祖先是高加索人。