title: RING domain mutations uncouple TRIM5α restriction of HIV-1 from inhibition of reverse transcription and acceleration of uncoating.
abstract: Rhesus TRIM5α (TRIM5α(rh)) is a cytosolic protein that potently restricts HIV-1 at an early postentry stage, prior to reverse transcription. The ability of TRIM5α(rh) to block HIV-1 infection has been correlated with a decrease of pelletable HIV-1 capsid during infection. To genetically dissect the ability of TRIM5α to block reverse transcription, we studied a set of TRIM5α(rh) RING domain mutants that potently restrict HIV-1 but allow the occurrence of reverse transcription. These TRIM5α(rh) RING variants blocked HIV-1 infection after reverse transcription but prior to integration, as suggested by the routing of nuclear viral DNA to circularization in the form of 2-long terminal repeat (2-LTR) circles. The folding of RING domain variants was similar to that of the wild type, as evaluated by nuclear magnetic resonance. RING domain changes that allowed the occurrence of reverse transcription were impaired in their ability to decrease the amount of pelletable capsid compared with wild-type TRIM5α. Similar effects of this particular group of mutations were observed with human TRIM5α inhibition of N-tropic murine leukemia virus (N-MLV). Interestingly, TRIM5α(rh) RING domain variants also prevented the degradation of TRIM5α(rh) that occurs following cell entry of HIV-1. These data correlated the block of reverse transcription with the ability of TRIM5α to accelerate uncoating. Collectively, these results suggest that TRIM5α(rh) blocks HIV-1 reverse transcription by inducing premature viral uncoating in target cells.
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine Bronx, New York, USA.
authors: Amanda
authors: A
authors: Roa
authors: Fumiaki
authors: F
authors: Hayashi
authors: Yang
authors: Y
authors: Yang
authors: Maritza
authors: M
authors: Lienlaf
authors: Jing
authors: J
authors: Zhou
authors: Jiong
authors: J
authors: Shi
authors: Satoru
authors: S
authors: Watanabe
authors: Takanori
authors: T
authors: Kigawa
authors: Shigeyuki
authors: S
authors: Yokoyama
authors: Christopher
authors: C
authors: Aiken
authors: Felipe
authors: F
authors: Diaz-Griffero
mesh_terms: D000818:Animals; D000090103:Antiviral Restriction Factors; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015342:DNA Probes; D004285:Dogs; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D048348:Reverse Transcription; D060168:Thymocytes / Q000821:virology; D014158:Transcription, Genetic; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D057646:Virus Uncoating
chemical_list: D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D015342:DNA Probes; D011506:Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; C482587:TRIM5(alpha) protein, rhesus monkey; D044767:Ubiquitin-Protein Ligases