RING domain mutations uncouple TRIM5α restriction of HIV-1 from inhibition of reverse transcription and acceleration of uncoating

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

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55 Scopus citations

Abstract

Rhesus TRIM5α (TRIM5αrh) is a cytosolic protein that potently restricts HIV-1 at an early postentry stage, prior to reverse transcription. The ability of TRIM5αrh 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 TRIM5αrh RING domain mutants that potently restrict HIV-1 but allow the occurrence of reverse transcription. These TRIM5αrh 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, TRIM5αrh RING domain variants also prevented the degradation of TRIM5αrh that occurs following cell entry of HIV-1. These data correlated the block of reverse transcription with the ability of TRIM5_ to accelerate uncoating. Collectively, these results suggest that TRIM5αrh blocks HIV-1 reverse transcription by inducing premature viral uncoating in target cells.

Original languageEnglish (US)
Pages (from-to)1717-1727
Number of pages11
JournalJournal of virology
Volume86
Issue number3
DOIs
StatePublished - Feb 1 2012

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ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

Roa, A., Hayashi, F., Yang, Y., Lienlaf, M., Zhou, J., Shi, J., Watanabe, S., Kigawa, T., Yokoyama, S., Aiken, C., & Diaz-Griffero, F. (2012). RING domain mutations uncouple TRIM5α restriction of HIV-1 from inhibition of reverse transcription and acceleration of uncoating. Journal of virology, 86(3), 1717-1727. https://doi.org/10.1128/JVI.05811-11