Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection
Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection
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DOI：
10.1016/s0092-8674(00)80110-5
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发表时间：
1996-08-09
期刊：
影响因子：
64.5
通讯作者：
Landau, NR
中科院分区：
文献类型：
--
作者：
Liu, R;Paxton, WA;Landau, NR
极少数人多次暴露于HIV-1，但仍然未受感染。其中两个个体的CD 4（+）T细胞，命名为EU 2和EU 3，在体外对原代嗜巨噬细胞病毒的进入具有高度抗性，但容易被转化的T细胞系适应病毒感染。我们在这里报告这种抗性的遗传基础。我们发现EU 2和EU 3在CKR-5中有一个纯合缺陷，CKR-5是最近描述的主要HIV-1分离株的辅助受体的编码基因。这些人似乎遗传了一个有缺陷的CKR-5等位基因，其中包含一个内部32个碱基对缺失。编码的蛋白质被严重截短，在细胞表面无法检测到。令人惊讶的是，这种缺陷在受影响的个体中没有明显的表型。因此，CKR-5等位基因存在于人群中似乎可以保护纯合子个体免受HIV-1的性传播。杂合子个体在某些群体中相当常见（接近20%）。这些发现表明CKR-5在HIV-1传播中的重要性，并表明靶向HIV-1-CKR-5相互作用可能提供预防或减缓疾病进展的方法。
Rare individuals have been multiply exposed to HIV-1 but remain uninfected. The CD4(+) T-cells of two of these individuals, designated EU2 and EU3, are highly resistant in vitro to the entry of primary macrophage-tropic virus but are readily infectable with transformed T-cell line adapted viruses. We report here on the genetic basis of this resistance. We found that EU2 and EU3 have a homozygous defect in CKR-5, the gene encoding the recently described coreceptor for primary HIV-1 isolates. These individuals appear to have inherited a defective CKR-5 allele that contains an internal 32 base pair deletion. The encoded protein is severely truncated and cannot be detected at the cell surface. Surprisingly, this defect has no obvious phenotype in the affected individuals. Thus, a CKR-5 allele present in the human population appears to protect homozygous individuals from sexual transmission of HIV-1. Heterozygous individuals are quite common (similar to 20%) in some populations. These findings indicate the importance of CKR-5 in HIV-1 transmission and suggest that targeting the HIV-1-CKR-5 interaction may provide a means of preventing or slowing disease progression.