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RING Domain Mutations Uncouple TRIM5α Restriction of HIV-1 from Inhibition of Reverse Transcription and Acceleration of Uncoating

2011; American Society for Microbiology; Volume: 86; Issue: 3 Linguagem: Inglês

10.1128/jvi.05811-11

1098-5514

Amanda Roa, Fumiaki Hayashi, Yang Yang, Maritza Lienlaf, Jing Zhou, Jiong Shi, Satoru Watanabe, T. Kigawa, Shigeyuki Yokoyama, Christopher Aiken, Felipe Diaz‐Griffero,

Herpesvirus Infections and Treatments

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.