title: Rhesus monkey TRIM5alpha restricts HIV-1 production through rapid degradation of viral Gag polyproteins.
abstract: Mammalian cells have developed diverse strategies to restrict retroviral infection. Retroviruses have therefore evolved to counteract such restriction factors, in order to colonize their hosts. Tripartite motif-containing 5 isoform-alpha (TRIM5alpha) protein from rhesus monkey (TRIM5alpharh) 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. TRIM5alpha 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. As TRIM5alpharh targets incoming mature HIV-1 capsid, but not precursor Gag, it was assumed that TRIM5alpharh did not affect HIV-1 production. Here we provide evidence that TRIM5alpharh, but not its human ortholog (TRIM5alphahu), 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 TRIM5alpharh 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.
authors: Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors: Ryuta
authors: R
authors: Sakuma
authors: Josh A
authors: JA
authors: Noser
authors: Seiga
authors: S
authors: Ohmine
authors: Yasuhiro
authors: Y
authors: Ikeda
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015683:Gene Products, gag / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D007668:Kidney; D008253:Macaca mulatta; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D044767:Ubiquitin-Protein Ligases; D014779:Virus Replication
chemical_list: D015683:Gene Products, gag; D011506:Proteins; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases