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Association of TRIMCyp and TRIM5α from assam macaques leads to a functional trade-off between HIV-1 and N-MLV inhibition

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Science China(Life Sciences) 2018年第8期61卷 954-965页

作者： Dan Mu Jia-Wu Zhu Feng-Liang Liu Hong-Yi Zheng Yong-Tang Zheng 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 Kunming Primate Research Center Chinese Academy of Sciences Kunming 650223 China

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 TR1M5-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 amTRIM5αc Although both proteins potently restricted the replication of HIV-1, only amTRIM5αt inhibited N-MLV. Remarkably, cellular anti-HIV-1 activity increased when amTRIMCyp and amTRIM5αt were coexpressed, indicating a synergistic block of HIV-1 replication. Consistently, PMBCs from heterozygous amTRIM50t/TRIMCyp showed stronger resistance to HIV-1 infection than those from amTRIM5a/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.

关键词： TRIMCyp/TRIM5α assam macaque HIV-1 N-MLV functional trade-off

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