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

作　　者：Dan Mu Jia-Wu Zhu Feng-Liang Liu Hong-Yi Zheng Yong-Tang Zheng 

机构地区：[1]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 [2]Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China [3]Kunming Primate Research Center, Chinese Academy of Sciences, Kunming 650223, China

出　　处：《Science China(Life Sciences)》2018年第8期954-965,共12页中国科学（生命科学英文版）

基　　金：supported by grants from the National Natural Science Foundation of China (81471620, 81671627, 81571606, 81172876, U0832601);the 13th Five-Year Key Scientific and Technological Program of China (2017ZX10304402-002-004, 2017ZX10202102-001-005);the Knowledge Innovation Program of the Chinese Academy of Sciences (KJZD-EW-L1002, KSCX2-EW-R-13);the National Key Research & Development Plan (2016YFC1201000);the National Basic Research Program of China (2012CBA01305)

摘　　要：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.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(am TRIMCyp), along with a TRIM5α allelic protein(am TRIM5α). Herein,we investigated the antiviral activity of am TRIMCyp and am TRIM5α individually, as well as their interaction and joint effects.am TRIMCyp showed a divergent restriction pattern from am TRIM5α. Although both proteins potently restricted the replication of HIV-1, only am TRIM5α inhibited N-MLV. Remarkably, cellular anti-HIV-1 activity increased when am TRIMCyp and am TRIM5α were coexpressed, indicating a synergistic block of HIV-1 replication. Consistently, PMBCs from heterozygous am TRIM5α/TRIMCyp showed stronger resistance to HIV-1 infection than those from am TRIM5α/TRIM5α homozygotes. The anti-HIV-1 synergistic effect was dependent on the am TRIMCyp-am TRIM5α interaction. In contrast, am TRIMCyp completely abrogated the anti-N-MLVactivity mediated by am TRIM5α, showing a dominant-negative effect, indicating that the generation of am TRIMCyp 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 

分 类 号：R373[医药卫生—病原生物学]