Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences/Key Laboratory of Bioactive Peptides of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, China.
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, 650204, China.
Sci China Life Sci. 2018 Aug;61(8):954-965. doi: 10.1007/s11427-018-9295-y. Epub 2018 Apr 26.
TRIM5α restricts retroviruses in a species-specific manner. Cyclophilin A was independently retrotransposed into the TRIM5 loci in different species, leading to the generation of antiviral TRIM5-cyclophilin A (TRIMCyp) proteins. Previously, we found that assam macaques express a TRIMCyp chimera (amTRIMCyp), along with a TRIM5α allelic protein (amTRIM5α). Herein, we investigated the antiviral activity of amTRIMCyp and amTRIM5α individually, as well as their interaction and joint effects. amTRIMCyp showed a divergent restriction pattern from amTRIM5α. Although both proteins potently restricted the replication of HIV-1, only amTRIM5α inhibited N-MLV. Remarkably, cellular anti-HIV-1 activity increased when amTRIMCyp and amTRIM5α were coexpressed, indicating a synergistic block of HIV-1 replication. Consistently, PMBCs from heterozygous amTRIM5α/TRIMCyp showed stronger resistance to HIV-1 infection than those from amTRIM5α/TRIM5α homozygotes. The anti-HIV-1 synergistic effect was dependent on the amTRIMCyp-amTRIM5α interaction. In contrast, amTRIMCyp completely abrogated the anti-N-MLV activity mediated by amTRIM5α, showing a dominant-negative effect, indicating that the generation of amTRIMCyp was involved in the trade-off between divergent restriction activities. Our results provide a new paradigm to study functional trade-offs mediated by allelic proteins, a theoretical basis for utilizing animal models with various TRIM5 alleles, as well as novel HIV-1 gene therapy strategies.
TRIM5α 以物种特异性方式限制逆转录病毒。亲环素 A 独立地被反向转移到不同物种的 TRIM5 基因座中，导致产生抗病毒的 TRIM5-亲环素 A（TRIMCyp）蛋白。先前，我们发现 Assam 猕猴表达一种 TRIMCyp 嵌合体（amTRIMCyp）以及一种 TRIM5α 等位蛋白（amTRIM5α）。在此，我们分别研究了 amTRIMCyp 和 amTRIM5α 的抗病毒活性及其相互作用和联合效应。amTRIMCyp 显示出与 amTRIM5α 不同的限制模式。尽管两种蛋白都能有效地限制 HIV-1 的复制，但只有 amTRIM5α 抑制 N-MLV。值得注意的是，当 amTRIMCyp 和 amTRIM5α 共表达时，细胞抗 HIV-1 活性增加，表明 HIV-1 复制受到协同抑制。一致地，杂合 amTRIM5α/TRIMCyp 的 PMBC 对 HIV-1 感染的抵抗力强于 amTRIM5α/TRIM5α 纯合子。抗 HIV-1 的协同效应依赖于 amTRIMCyp-amTRIM5α 的相互作用。相反，amTRIMCyp 完全消除了 amTRIM5α 介导的抗 N-MLV 活性，表现出显性负效应，表明 amTRIMCyp 的产生涉及到不同限制活性之间的权衡。我们的研究结果提供了一个新的范例，用于研究由等位基因蛋白介导的功能权衡，为利用具有各种 TRIM5 等位基因的动物模型提供了理论基础，以及新型 HIV-1 基因治疗策略。
