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 （TRIM...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.展开更多
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)+2 种基金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)
文摘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.
