Parallel evolution of CCR5-null phenotypes in humans and in a natural host of simian immunodeficiency virus
Parallel evolution of CCR5-null phenotypes in humans and in a natural host of simian immunodeficiency virus
复制标题
DOI：
10.1016/s0960-9822(07)00378-8
复制
发表时间：
1998-08-13
期刊：
影响因子：
9.2
通讯作者：
Grant, RM
中科院分区：
文献类型：
--
作者：
Palacios, E;Digilio, L;Grant, RM
人和恒河猴C-C趋化因子受体CCR5（Macaca mulatta）作为人类免疫缺陷病毒1型（HIV-1）嗜巨噬细胞株和所有已报道的猿猴免疫缺陷病毒（SIV）株进入细胞的主要辅助受体[1 - 6]，CCR 5的32 bp缺失等位基因纯合的人，导致无效表型，对HIV-1感染具有高度抗性[7 - 9]，促进了靶向CCR5的疗法和疫苗的开发。我们现在报告了一种新的CCR 5缺失等位基因，等位基因频率为0.04，在SIV（SIVsmm）的天然宿主-突变蛋白在细胞表面不表达，因此不作为病毒辅助受体发挥功能。缺失等位基因杂合的白眉猴的初级活化淋巴细胞在细胞表面表达的CCR 5显著减少。此外，SIV血清阳性率和病毒血症之间的CCR5杂合子和野生型动物是可比的。人类和白眉猴中CCR5无效等位基因的平行进化表明，类似的负选择压力对CCR5起作用，就像在需要CCR5致病的传染性病原体流行期间发生的那样。将黑白眉猴培育成缺失等位基因的纯合性，将有助于对CCR5在宿主防御和微生物致病中的上下文依赖性作用进行实验研究。(C)当前生物学出版物ISSN 0960 - 9822。
The C-C chemokine receptor CCR5 in humans and rhesus macaques (Macaca mulatta) serves as the primary coreceptor for cellular entry by macrophage-tropic strains of human immunodeficiency virus type 1 (HIV-1) and all reported strains of simian immunodeficiency virus (SIV) [1-6], Humans homozygous for a 32 bp deletion allele of CCR5, resulting in a null phenotype, are highly resistant to infection by HIV-1 [7-9], prompting development of therapies and vaccines targeting CCR5. We now report a novel deletion allele of CCR5, with an allele frequency of 0.04, in sooty mangabey monkeys (Cercocebus torguatus atys), a natural host of SIV (SIVsmm) [10]. The mutant protein was not expressed at the cell surface and accordingly did not function as a viral coreceptor, Primary activated lymphocytes from mangabeys heterozygous for the deletion allele expressed significantly less CCR5 on the cell surface. Moreover, SIV seroprevalence and viremia were comparable among CCR5 heterozygotes and wild-type animals. Parallel evolution of CCR5-null alleles in humans and sooty mangabeys suggests that similar negative selection pressures have acted against CCR5, as would occur during epidemics of infectious agents that require CCR5 for pathogenesis. Sooty mangabeys bred to homozygosity for the deletion allele will be useful for experimental studies on the context-dependent role of CCR5 in host defense and microbial pathogenesis. (C) Current Biology Publications ISSN 0960-9822.