Immunoproteasome activation enables human TRIM5α restriction of HIV-1

Type 1 interferon (IFN) suppresses viral replication by upregulating the expression of interferon-stimulated genes (ISGs) with diverse anti-viral properties1. The replication of human immunodeficiency virus type-1 (HIV-1) is naturally inhibited by IFN, with the steps between viral entry and chromosomal integration of viral DNA being notably susceptible2–5. The ISG myxovirus resistance 2 (MX2) has been defined as an effective post-entry inhibitor of HIV-1, but is only partially responsible for IFN’s suppressive effect6–8. Using siRNA-based library screening in IFNα-treated cells, we sought to characterize further ISGs that target the pre-integration phases of HIV-1 infection, and identified human tri-partite-containing motif 5α (TRIM5α) as a potent anti-HIV-1 restriction factor. Human TRIM5α, in contrast to many non-human orthologues, has not generally been ascribed significant HIV-1 inhibitory function, a finding attributed to ineffective recognition of cytoplasmic viral capsids by TRIM5α2,9,10. Here, we demonstrate that IFNα-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 (PA) 28 regulatory complex11–13, 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 anti-viral function in human cells and rationalize how TRIM5α participates in the immune control of HIV-1 infection.