Interferon-α (IFNα) induces the expression of interferon-stimulated genes (ISGs) that inhibit HIV-1 replication. Malim and colleagues set out to characterize human ISGs that suppress HIV-1 replication and identified well-established genes, such as those encoding IFN regulatory factor 9 or myxovirus resistance 2, as well as human tripartite-containing motif 5α (TRIM5α), a ubiquitin ligase that was previously thought not to be active against HIV-1. By contrast, non-human TRIM5α proteins have been shown to be HIV-1 restriction factors that target the early post-entry phases of infection. The authors now show that in the presence of IFNα, human TRIM5α suppresses HIV-1 infection. The inhibitory effect is regulated by the IFNα-mediated activation of the immunoproteasome; IFNα promotes the proteolytic turnover of TRIM5α and effective capsid-dependent inhibition of HIV-1 DNA synthesis and infection. Thus, the results suggest that TRIM5α contributes to the control of HIV-1 in infected humans.