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A B-box 2 surface patch important for TRIM5alpha self-association, capsid binding avidity, and retrovirus restriction

Felipe Diaz-Griffero1, Xu-rong Qin, Fumiaki Hayashi

  • 1Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

Journal of Virology
|August 7, 2009
PubMed

Insights

The TRIM5alpha protein

Area of Science:

  • Virology
  • Molecular Biology
  • Structural Biology

Background:

  • TRIM5alpha (tripartite motif protein) is a key antiviral factor.
  • Rhesus TRIM5alpha (TRIM5alpha(rh)) restricts human immunodeficiency virus type 1 (HIV-1) infection by recognizing the viral capsid.
  • The B-box 2 domain of TRIM5alpha is crucial for its HIV-1 restricting ability.

Purpose of the Study:

  • To elucidate the structural and functional role of the TRIM5alpha B-box 2 domain in HIV-1 restriction.
  • To investigate how mutations in the B-box 2 domain affect TRIM5alpha's interaction with the HIV-1 capsid and its antiviral activity.

Main Methods:

  • Nuclear magnetic resonance (NMR) spectroscopy was used to determine the structure of the TRIM5 B-box 2 domain.
  • Site-directed mutagenesis was employed to create TRIM5alpha(rh) B-box 2 mutants.
  • HIV-1 infection assays were performed to assess the antiviral activity of the mutants.
  • Analysis of TRIM5alpha(rh) turnover, cytoplasmic body formation, and self-association was conducted.

Main Results:

  • The NMR structure revealed an unusual hydrophobic patch (cluster 1) on the TRIM5 B-box 2 domain surface.
  • Mutations in cluster 1 or at arginine 121 significantly impaired HIV-1 restriction.
  • HIV-1 inhibition correlated strongly with higher-order self-association and capsid binding affinity.
  • TRIM5alpha(rh) half-life and cytoplasmic body formation were not directly linked to antiviral activity.

Conclusions:

  • The B-box 2 domain's ability to promote cooperative TRIM5alpha(rh) interactions with the HIV-1 capsid is a primary mechanism for restricting viral infection.
  • Specific structural features, like the hydrophobic patch, are critical for TRIM5alpha's antiviral function.
  • Understanding these interactions could inform strategies to enhance TRIM5alpha-mediated antiviral defense.

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