SUMOylation by the NSMCE2 component of SMC5/6 was required for the initiation but not maintenance of epigenetic silencing, as the ability of TAK-981 to prevent silencing was lost after 24 h post-infection even though TAK-981 retained the ability to deplete SUMO modifications from chromatinized, unintegrated HIV-1 DNA at later times. The gene discussed is SMC5; the disease is infection.