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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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.
KeywordsTRIMCyp/TRIM5α assam macaque HIV-1 N-MLV functional trade-off
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We thank Prof. Guang-Xia Gao (Institute of Biophysics, Chinese Academy of Sciences) for providing the HIV-1-GFP and NMLV- GFP packaging plasmids, Prof. Ce-Shi Chen (Kunming Institute of Zoology, Chinese Academy of Sciences) for providing the Myc-ub plasmid, Prof. Greg J. Towers (University College London) for the p8.91 G89V plasmid, and Ms. Huan Chen (Kunming Institute of Zoology) for the primers and probes used in qPCR. We thank the Kunming Primate Research Center, Chinese Academy of Sciences, for providing macaque samples. This work was 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-L10-02, KSCX2-EW-R-13), the National Key Research & Development Plan (2016YFC1201000), and the National Basic Research Program of China (2012CBA01305).
- Goldstone, D.C., Walker, P.A., Calder, L.J., Coombs, P.J., Kirkpatrick, J., Ball, N.J., Hilditch, L., Yap, M.W., Rosenthal, P.B., Stoye, J.P., et al. (2014). Structural studies of postentry restriction factors reveal antiparallel dimers that enable avid binding to the HIV-1 capsid lattice. Proc Natl Acad Sci USA 111, 9609–9614.CrossRefPubMedGoogle Scholar
- Kuang, Y.Q., Tang, X., Liu, F.L., Jiang, X.L., Zhang, Y.P., Gao, G., and Zheng, Y.T. (2009). Genotyping of TRIM5 locus in northern pig-tailed macaques (Macaca leonina), a primate species susceptible to Human Immunodeficiency Virus type 1 infection. Retrovirology 6, 58.CrossRefPubMedPubMedCentralGoogle Scholar
- Reynolds, M.R., Sacha, J.B., Weiler, A.M., Borchardt, G.J., Glidden, C.E., Sheppard, N.C., Norante, F.A., Castrovinci, P.A., Harris, J.J., Robertson, H.T., et al. (2011). The TRIM5a genotype of rhesus macaques affects acquisition of simian immunodeficiency virus SIVsmE660 infection after repeated limiting-dose intrarectal challenge. J Virol 85, 9- 637–9640.CrossRefGoogle Scholar
- Roa, A., Hayashi, F., Yang, Y., Lienlaf, M., Zhou, J., Shi, J., Watanabe, S., Kigawa, T., Yokoyama, S., Aiken, C., et al. (2012). RING domain mutations uncouple TRIM5a restriction of HIV-1 from inhibition of reverse transcription and acceleration of uncoating. J Virol 86, 1717–1727.CrossRefPubMedPubMedCentralGoogle Scholar