Copy number variation of CCL3-like genes affects rate of progression to simian-AIDS in Rhesus Macaques (Macaca mulatta).
Copy number variation of CCL3-like genes affects rate of progression to simian-AIDS in Rhesus Macaques (Macaca mulatta).
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DOI：
10.1371/journal.pgen.1000346
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发表时间：
2009-01
期刊：
影响因子：
4.5
通讯作者：
Bustamante CD
中科院分区：
文献类型：
--
作者：
Degenhardt JD;de Candia P;Chabot A;Schwartz S;Henderson L;Ling B;Hunter M;Jiang Z;Palermo RE;Katze M;Eichler EE;Ventura M;Rogers J;Marx P;Gilad Y;Bustamante CD
宿主免疫基础基因的变异可导致人类对HIV感染易感性的显著差异。尽管严重依赖非人类灵长类动物作为艾滋病毒/艾滋病的模型，但人们对哪些宿主因素是共同的，哪些是特定灵长类动物谱系所独有的知之甚少。在这里，我们研究了ccl3样基因（CCL3L）的拷贝数变异（CNV）是否也是恒河猴猿类艾滋病发病时间的决定因素，CCL3L是人类HIV/AIDS易感性和细胞介导的免疫反应的关键遗传宿主因子。通过对57只实验感染SIVmac的恒河猴进行回顾性研究，我们发现CCL3L拷贝数较低与病程越快相关，CCL3L拷贝数较低解释了类人猿艾滋病时间变异的约18% （p<0.001）。我们还发现，CCL3L基因拷贝数在恒河猴亚群之间存在显著差异（p<10−6），印度猕猴的CCL3L基因拷贝数平均是中国猕猴的一半。最后，我们证实了CCL3L在人类和黑猩猩中表现出可变的拷贝数，并报道了另外三种灵长类动物中CCL3L的CNV。基于我们的研究结果，我们认为：(1)种群水平拷贝数的差异可能解释了之前报道的中国源猕猴感染后存活时间较长的观察结果；(2)在恒河猴SIV疫苗试验中，CCL3L拷贝数分层将增加功率并减少由于非疫苗相关的生存差异而产生的噪音；(3)CCL3L CNV是灵长类动物免疫应答的祖先组成部分，因此，拷贝数变异不是由HIV或SIV本身驱动的。研制艾滋病毒/艾滋病疫苗是一个紧迫的全球性问题。恒河猴仍然是测试潜在人类疫苗的主要模型；然而，人们对人类和恒河猴参与HIV/AIDS反应的宿主基因的异同知之甚少。了解这些相同点和/或不同点，将有助于更有效地测试对人类有益的疫苗。在这里，我们描述了ccl3样基因（CCL3L）拷贝数的变化在恒河猴SIV进展率中的作用。这些基因的拷贝数变异（CNV）先前已被证明在人类艾滋病毒的易感性和进展中发挥作用。我们的研究结果表明，CCL3L拷贝数较低的猴子个体进步更快。在恒河猴疫苗试验中考虑CCL3L CNV将提高研究人员解释生存数据的能力。
Variation in genes underlying host immunity can lead to marked differences in susceptibility to HIV infection among humans. Despite heavy reliance on non-human primates as models for HIV/AIDS, little is known about which host factors are shared and which are unique to a given primate lineage. Here, we investigate whether copy number variation (CNV) at CCL3-like genes (CCL3L), a key genetic host factor for HIV/AIDS susceptibility and cell-mediated immune response in humans, is also a determinant of time until onset of simian-AIDS in rhesus macaques. Using a retrospective study of 57 rhesus macaques experimentally infected with SIVmac, we find that CCL3L CNV explains approximately 18% of the variance in time to simian-AIDS (p<0.001) with lower CCL3L copy number associating with more rapid disease course. We also find that CCL3L copy number varies significantly (p<10−6) among rhesus subpopulations, with Indian-origin macaques having, on average, half as many CCL3L gene copies as Chinese-origin macaques. Lastly, we confirm that CCL3L shows variable copy number in humans and chimpanzees and report on CCL3L CNV within and among three additional primate species. On the basis of our findings we suggest that (1) the difference in population level copy number may explain previously reported observations of longer post-infection survivorship of Chinese-origin rhesus macaques, (2) stratification by CCL3L copy number in rhesus SIV vaccine trials will increase power and reduce noise due to non-vaccine-related differences in survival, and (3) CCL3L CNV is an ancestral component of the primate immune response and, therefore, copy number variation has not been driven by HIV or SIV per se. Development of vaccines for HIV/AIDS is a pressing global issue. The rhesus monkey remains the primary model for testing potential human vaccines; however, little is known about similarities and differences in host genes involved in HIV/AIDS response in humans and rhesus monkeys. Understanding these similarities and/or differences should allow more efficient testing of vaccines beneficial to humans. Here we describe the role that variation in the number of copies of CCL3-like genes (CCL3L) plays in SIV progression rates in rhesus monkeys. Copy number variation (CNV) of these genes has previously been shown to play a role in susceptibility and progression of HIV in humans. Our results suggest that individual monkeys with lower CCL3L copy number progress more rapidly. Accounting for CCL3L CNV in rhesus vaccine trials will improve researchers' abilities to interpret survival data.
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