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Rhesus monkey TRIM5α restricts HIV-1 production through rapid degradation of viral Gag polyproteins

Nature Medicine volume 13, pages 631–635 (2007)Cite this article

Abstract

Mammalian cells have developed diverse strategies to restrict retroviral infection1,2,3,4,5. Retroviruses have therefore evolved to counteract such restriction factors, in order to colonize their hosts4,6. Tripartite motif-containing 5 isoform-α (TRIM5α) protein from rhesus monkey (TRIM5αrh) 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 disassembly7,8. TRIM5α 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 restriction8,9,10,11. As TRIM5αrh targets incoming mature HIV-1 capsid, but not precursor Gag12, it was assumed that TRIM5αrh did not affect HIV-1 production. Here we provide evidence that TRIM5αrh, but not its human ortholog (TRIM5αhu), 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 TRIM5αrh 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.

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Figure 1: TRIM5αrh specifically restricts HIV-1 production in rhesus monkey cells.
Figure 2: TRIM5αrh blocks HIV-1 production through rapid degradation of Gag.
Figure 3: Encapsidation of TRIM5αrh in VLPs.
Figure 4: The RBCC domain of TRIM5αrh is responsible for the anti–HIV-1 activity.

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Acknowledgements

We thank G.J. Towers (University College London) for retroviral vector plasmids expressing TRIM5αrh and TRIM5αagm. We thank M.K. Collins (University College London) for pCNC-SYNGP, D. Trono (Ecole Polytechnique Federale de Lausanne) for pMD-G and pCMV-R8.91, and H. Hoshino (Gunma University) for pGun1WT. The following reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases (NIAID). US National Institutes of Health: GHOST(3)R3/X4/R5 cells (V.N. KewalRamani and D.R. Littman, New York University School of Medicine), pLPCX-TRIM5αhu-HA (J. Sodroski and M. Stremlau, Harvard Medical School), monoclonal antibodies to HIV-1 p24 AG3.0 (J. Allan, Southwestern Foundation for Biomedical Research) and 183-H12-5C (B. Chesebro and K. Wehrly, NIAID), pNL4-3 (M. Martin, NIAID), p89.6 (R.G. Collman, University of Pennsylvania School of Medicine), pSIVMAC1A11 (P. Luciw, University of California, Davis) and pSIVAGMtan-1 (M. Soares and B. Hahn, University of Alabama at Birmingham). We thank S. Vongpunsawad for technical support, and R. Cattaneo, E.M. Poeschla and S.J. Russell for helpful discussions. This work was supported by the Mayo Foundation (to Y.I.).

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Authors and Affiliations

  1. Molecular Medicine Program, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    Ryuta Sakuma, Josh A Noser, Seiga Ohmine & Yasuhiro Ikeda

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  1. Ryuta Sakuma
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Contributions

R.S. and Y.I. designed the experiments; R.S. and S.O. performed the experiments; J.A.N. contributed new reagents; R.S. and Y.I. analyzed data; and Y.I. supervised the project and wrote the manuscript.

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Correspondence to Yasuhiro Ikeda.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Transfection of the TRIM5αrh-specific siRNA (T5α) reduces the levels of TRIM5αrh mRNA and increases the permissivity of the cells to a GFP-carrying HIV-1 vector. (PDF 24 kb)

Supplementary Fig. 2

The TRIM5α-specific siRNA reduces the level of HA-tagged TRIM5α protein expressed from pRhT5α, but not from pRhT5α-ESCAPE. (PDF 24 kb)

Supplementary Fig. 3

Disruption of TRIM5αrh mRNA by different shRNA constructs results in increased HIV-1 production in FrhK4 cells. (PDF 27 kb)

Supplementary Fig. 4

TRIM5arh expression does not affect the levels of HIV-1-specific transcripts. (PDF 29 kb)

Supplementary Fig. 5

pH-GP, which expresses codon-optimized HIV-1 gag-pol genes, produces more Gag proteins than conventional Gag-Pol expression plasmid, pCMV-R8.91. (PDF 19 kb)

Supplementary Fig. 6

Cumulative ELISpot data for lung anti-elastin antibody-secreting cells in Control (n=6) and Emphysema (n=6) groups. (PDF 65 kb)

Supplementary Fig. 7

The TRIM5αrh B30.2(SPRY) domain is not required for the restriction. (PDF 37 kb)

Supplementary Fig. 8

TRIM5αagm blocks HIV-1 production. Reduced FoxP3 expression and IL-10 in emphysema. (PDF 85 kb)

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Sakuma, R., Noser, J., Ohmine, S. et al. Rhesus monkey TRIM5α restricts HIV-1 production through rapid degradation of viral Gag polyproteins. Nat Med 13, 631–635 (2007). https://doi.org/10.1038/nm1562

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