Frequent substitution polymorphisms in African green monkey CCR5 cluster at critical sites for infections by simian immunodeficiency virus SIVagm, implying ancient virus-host coevolution
Frequent substitution polymorphisms in African green monkey CCR5 cluster at critical sites for infections by simian immunodeficiency virus SIVagm, implying ancient virus-host coevolution
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DOI：
10.1128/jvi.75.18.8449-8460.2001
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发表时间：
2001-09-01
影响因子：
5.4
通讯作者：
Kabat, D
中科院分区：
文献类型：
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作者：
Kuhmann, SE;Madani, N;Kabat, D
与人类不同，几种灵长类物种被认为自古以来就携带有猴免疫缺陷病毒(SIV)。特别是，地理上分散的非洲绿猴(AGM)物种都感染了高度多样化的SIVagm病毒(超过50%的性成熟个体)，没有明显的疾病，这意味着祖猴在传播之前就感染了SIVagm病毒。如果这是正确的，预计AGM在宿主基因中积累了频繁的与抗药性相关的多态，这些多态对SIV复制非常重要。因此，我们分析了来自四个物种不同种群的26个AGM(52个等位基因)的CCR5辅助受体的编码序列。这些样本包含29个非同义编码改变和只有15个同义核苷酸替换，这意味着强烈的功能选择。此外，24个氨基酸替换紧密地聚集在CCR5的氨基端(马鞭草的D13N和Tantalus的Y14N)或第一个胞外环(所有物种的Q93R和Q93K)。Y14N替换在12只野生出生的非洲Tantalus中非常频繁，其中7只猴子为纯合子，4只为杂合子。虽然其中两个杂合子和唯一的野生型纯合子自然感染了SIVagm，但Y14N纯合子没有自然感染。对SIVagm的局部感染性分析表明，所有被测试的SIVagm都有效地使用CCR5作为辅助受体，它们也使用效率较低的CXCR6(STRL33/Bonzo)和GPR15(Bob)，但不使用CXCR4。有趣的是，AGM CCR5中的D13N、Y14N、Q93R和Q93K替换在体外都对SIVagm分离株的感染有很强的抑制作用。Y14N取代消除了对感染很重要的酪氨酸硫化位点，并导致该位置的部分N-连接糖基化(即60%的效率)。然而，CCR5(Y14N)缺乏N-连接的寡糖，它与趋化因子MIP-1β以正常的亲和力结合，并在信号转导中充分活跃。同样，D13N和Q93R替换不干扰信号转导。因此，AGM CCR5中常见的替换多态在很大程度上保留了趋化因子信号的同时，强烈地抑制了SIVagm感染。相比之下，人类CCR5基因的多态性相对较少，氨基酸替换是随机分布的，通常对辅助受体功能没有影响。这些结果支持AGMS和SIVagm病毒的古老共同进化，并将AGMS确立为一个高度信息量的模型，用于了解在免疫缺陷病毒感染中发挥关键作用的宿主蛋白。
In contrast to humans, several primate species are believed to have harbored simian immunodeficiency viruses (SIVs) since ancient times. In particular, the geographically dispersed species of African green monkeys (AGMs) are all infected with highly diversified SIVagm viruses at high prevalences (greater than 50% of sexually mature individuals) without evident diseases, implying that the progenitor monkeys were infected prior to their dispersal. If this is correct, AGMs would be expected to have accumulated frequent resistance-conferring polymorphisms in host genes that are important for SIV replication. Accordingly, we analyzed the coding sequences of the CCR5 coreceptors from 26 AGMs (52 alleles) in distinct populations of the four species. These samples contained 29 nonsynonymous coding changes and only 15 synonymous nucleotide substitutions, implying intense functional selection. Moreover, 24 of the resulting amino acid substitutions were tightly clustered in the CCR5 amino terminus (D13N in the vervets and Y14N in the tantalus species) or in the first extracellular loop (Q93R and Q93K in all species). The Y14N substitution was extremely frequent in the 12 wild-born African tantalus, with 7 monkeys being homozygous for this substitution and 4 being heterozygous. Although two of these heterozygotes and the only wild-type homozygote were naturally infected with SIVagm, none of the Y14N homozygotes were naturally infected. A focal infectivity assay for SIVagm indicated that all five tested SIVagms efficiently use CCR5 as a coreceptor and that they also use CXCR6 (STRL33/Bonzo) and GPR15 (BOB) with lower efficiencies but not CXCR4. Interestingly, the D13N, Y14N, Q93R, and Q93K substitutions in AGM CCR5 all strongly inhibited infections by the SIVagm, isolates in vitro. The Y14N substitution eliminates a tyrosine sulfation site that is important for infections and results in partial N-linked glycosylation (i.e., 60% efficiency) at this position. Nevertheless, the CCR5(Y14N) component that lacks an N-linked oligosaccharide binds the chemokine MIP-1 beta with a normal affinity and is fully active in signal transduction. Similarly, D13N and Q93R substitutions did not interfere with signal transduction. Thus, the common substitution polymorphisms in AGM CCR5 strongly inhibit SIVagm infections while substantially preserving chemokine signaling. In contrast, polymorphisms of human CCR5 are relatively infrequent, and the amino acid substitutions are randomly situated and generally without effects on coreceptor function. These results support an ancient coevolution of AGMs and SIVagm viruses and establish AGMs as a highly informative model for learning about host proteins that play critical roles in immunodeficiency virus infections.