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Immunoproteasome activation enables human TRIM5α restriction of HIV-1

Abstract

Type 1 interferon suppresses viral replication by upregulating the expression of interferon-stimulated genes with diverse antiviral properties1. The replication of human immunodeficiency virus type 1 (HIV-1) is naturally inhibited by interferon, with the steps between viral entry and chromosomal integration of viral DNA being notably susceptible2,3,4,5. The interferon-stimulated gene myxovirus resistance 2 has been defined as an effective postentry inhibitor of HIV-1, but is only partially responsible for interferon’s suppressive effect6,7,8. Using small interfering RNA-based library screening in interferon-α-treated cells, we sought to characterize further interferon-stimulated genes that target the pre-integration phases of HIV-1 infection, and identified human tripartite-containing motif 5α (TRIM5α) as a potent anti-HIV-1 restriction factor. Human TRIM5α, in contrast with many nonhuman orthologues, has not generally been ascribed substantial HIV-1 inhibitory function, a finding attributed to ineffective recognition of cytoplasmic viral capsids by TRIM5α2,9,10. Here, we demonstrate that interferon-α-mediated stimulation of the immunoproteasome, a proteasome isoform mainly present in immune cells and distinguished from the constitutive proteasome by virtue of its different catalytic β-subunits, as well as the proteasome activator 28 regulatory complex11,12,13, and the associated accelerated turnover of TRIM5α underpin the reprogramming of human TRIM5α for effective capsid-dependent inhibition of HIV-1 DNA synthesis and infection. These observations identify a mechanism for regulating human TRIM5α antiviral function in human cells and rationalize how TRIM5α participates in the immune control of HIV-1 infection.

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Fig. 1: Human TRIM5α is a key effector in the IFN-induced suppression of HIV-1 infection.
Fig. 2: HIV-1 CA determines IFN-α-induced restriction by human TRIM5α.
Fig. 3: HIV-1 restriction by human TRIM5α requires a functional proteasome system.
Fig. 4: HIV-1 restriction by human TRIM5α is regulated by the immunoproteasome.

Data availability

The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We thank D. Pollpeter, M. Dicks, S. Papaioannou, C. Wells and S. Wolinsky for the generous provision of reagents and helpful discussions. The work was supported by the UK Medical Research Council (grant no. G1000196), the Wellcome Trust (grant no. 106223/Z/14/Z), and the Department of Health via a National Institute for Health Research comprehensive Biomedical Research Centre award to Guy’s and St. Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. J.M.J.-G. is a Long-Term Fellow of the European Molecular Biology Organization (EMBO) (ALTF 663-2016).

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J.M.J.-G., L.A., and M.H.M. conceived the siRNA screen. J.M.J.-G. and M.H.M. designed the study and wrote the manuscript with input from all co-authors. J.M.J.-G. carried out the experiments and analysed the data. L.A. and G.B. contributed to the execution of experiments and provided reagents. M.H.M. supervised all aspects of the project.

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Correspondence to Michael H. Malim.

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Jimenez-Guardeño, J.M., Apolonia, L., Betancor, G. et al. Immunoproteasome activation enables human TRIM5α restriction of HIV-1. Nat Microbiol 4, 933–940 (2019). https://doi.org/10.1038/s41564-019-0402-0

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