Cellular TRIM33 restrains HIV-1 infection by targeting viral integrase for proteasomal degradation.

Productive HIV-1 replication requires viral integrase (IN), which catalyzes integration of theviral genome into the host cell DNA. IN, however, is short lived and is rapidly degraded bythe host ubiquitin-proteasome system. To identify the cellular factors responsible for HIV-1IN degradation, we performed a targeted RNAi screen using a library of siRNAs against allcomponents of the ubiquitin-conjugation machinery using high-content microscopy. Herewe report that the E3 RING ligase TRIM33 is a major determinant of HIV-1 IN stability. CD4-positive cells with TRIM33 knock down show increased HIV-1 replication and proviral DNAformation, while those overexpressing the factor display opposite effects. Knock down ofTRIM33 reverts the phenotype of an HIV-1 molecular clone carrying substitution of INserine 57 to alanine, a mutation known to impair viral DNA integration. Thus, TRIM33 acts as a cellular factor restricting HIV-1 infection by preventing provirus formation