Rhesus monkey TRIM5α restricts HIV-1 production through rapid degradation of viral Gag polyproteins

Mammalian cells have developed diverse strategies to restrict retroviral infection(1-5). Retroviruses have therefore evolved to counteract such restriction factors, in order to colonize their hosts(4,6). Tripartite motif-containing 5 isoform-alpha (TRIM5 alpha) protein from rhesus monkey (TRIM5 alpha rh) restricts human immunodeficiency virus type 1 (HIV-1) infection at a postentry, preintegration stage in the viral life cycle, by recognizing the incoming capsid and promoting its premature disassembly(7,8). TRIM5 alpha comprises an RBCC (RING, B-box 2 and coiled-coil motifs) domain and a B30.2(SPRY) domain. Sequences in the B30.2( SPRY) domain dictate the potency and specificity of the restriction(8-11). As TRIM5 alpha rh targets incoming mature HIV-1 capsid, but not precursor Gag(12), it was assumed that TRIM5 alpha rh did not affect HIV-1 production. Here we provide evidence that TRIM5 alpha rh, but not its human ortholog (TRIM5 alpha hu), blocks HIV-1 production through rapid degradation of HIV-1 Gag polyproteins. The specificity for this restriction is determined by sequences in the RBCC domain. Our observations suggest that TRIM5 alpha rh interacts with HIV-1 Gag during or before Gag assembly through a mechanism distinct from the well-characterized postentry restriction. This finding demonstrates a cellular factor blocking HIV-1 production by actively degrading a viral protein. Further understanding of this previously unknown restriction mechanism may reveal new targets for future anti-HIV-1 therapy.