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Restriction of HIV-1 and other retroviruses by TRIM5

Abstract

Mammalian cells express a variety of innate immune proteins — known as restriction factors — which defend against invading retroviruses such as HIV-1. Two members of the tripartite motif protein family — TRIM5α and TRIMCyp — were identified in 2004 as restriction factors that recognize and inactivate the capsid shell that surrounds and protects the incoming retroviral core. Research on these TRIM5 proteins has uncovered a novel mode of non-self recognition that protects against cross-species transmission of retroviruses. Our developing understanding of the mechanism of TRIM5 restriction underscores the concept that core uncoating and reverse transcription of the viral genome are coordinated processes rather than discrete steps of the post-entry pathway of retrovirus replication. In this Review, we provide an overview of the current state of knowledge of the molecular mechanism of TRIM5-mediated restriction, highlight recent advances and discuss implications for the development of capsid-targeted antiviral therapeutics.

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Fig. 1: The early stages of HIV-1 replication.
Fig. 2: Structural and functional properties of TRIM5.
Fig. 3: Mechanism of core recognition by TRIM5.
Fig. 4: Mechanism of TRIM5-mediated restriction.
Fig. 5: TRIM5-mediated signalling.

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Acknowledgements

The authors thank E. M. Campbell, W. E. Diehl, J. Luban and W. I. Sundquist for discussions. Work on TRIM5 in the laboratories of the authors is supported by grants P50-GM082545 (B.K.G.-P.) and R01-GM112508 (O.P.) from the National Institutes of Health.

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Both authors researched data for the article, contributed substantially to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Barbie K. Ganser-Pornillos or Owen Pornillos.

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Nature Reviews Microbiology thanks L. Berthoux, F. Diaz-Griffero and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Recognition

In the context of immune surveillance and antiviral defence, this refers to the ability of the host to distinguish its own (self) macromolecules from those of others (non-self) such as viruses and pathogens.

Viral capsid

A protein shell that surrounds (encapsidates) and protects the viral genome.

Viral core

In retroviruses, this refers to the viral capsid and its contents (the genome and its associated proteins and enzymes). The core is a diffusible object that (in the case of HIV-1) can travel from the site of entry at the plasma membrane to the nucleus.

Ubiquitylation

A multienzyme process of modifying primary amines in target proteins (typically lysine side chains or free amino termini) with the small protein ubiquitin.

Lentiviruses

Viruses belonging to a genus of retroviruses that have the ability to infect non-dividing cells, and have therefore evolved mechanisms to directly deliver their genomes to an intact nucleus.

Fullerene cone

The geometric architecture of the HIV-1 capsid. In general, a closed fullerene shell is made up of multiple hexagons and 12 pentagons.

Coiled-coil

A quaternary protein fold made up of one or more α-helices that oligomerize and coil around each other in the form of a superhelix.

Scaffolds

A general term that applies to a protein whose function is to bind other proteins, thereby directing the spatial and temporal juxtaposition of the binding partners and influencing their interactions.

Restriction factor

A protein that inhibits (or restricts) virus replication in cells. In general, these proteins exhibit sequence signatures of positive selective pressure. Viruses typically evolve adaptations that mitigate the antiviral effects of these proteins.

Antiviral state

A general term that refers to the cellular environment on induction of interferon-stimulated genes, which collectively act to inhibit virus infection.

Immunoproteasome

A specialized kind of proteasome that is upregulated by interferon. It is distinguished from the constitutive proteasome by different catalytic subunits and its dependence on the proteasome activator 28 regulatory subunit.

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Ganser-Pornillos, B.K., Pornillos, O. Restriction of HIV-1 and other retroviruses by TRIM5. Nat Rev Microbiol 17, 546–556 (2019). https://doi.org/10.1038/s41579-019-0225-2

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