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Review
. 2019 Sep;17(9):546-556.
doi: 10.1038/s41579-019-0225-2. Epub 2019 Jul 16.

Restriction of HIV-1 and other retroviruses by TRIM5

Affiliations
Review

Restriction of HIV-1 and other retroviruses by TRIM5

Barbie K Ganser-Pornillos et al. Nat Rev Microbiol. 2019 Sep.

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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Figures

Figure 1 |
Figure 1 |. The early stages of HIV-1 replication.
The mature HIV-1 virus particle consists of the viral core surrounded by the viral membrane (envelope). The membrane contains embedded envelope protein Env (composed of gp120 and gp41 subunits) and MA proteins that make up the matrix layer. The viral core consists of the capsid and its contents. The capsid is a protein shell comprising around 1,500 copies of CA. Inside the capsid are the viral RNA genome, bound nucleocapsid (NC) proteins and the viral enzymes reverse transcriptase (RT) and integrase (IN). To initiate infection, Env binds to the CD4 receptor and co-receptor (CCR5 or CXCR4) on the host cell surface. Fusion of the viral and cellular membranes releases the viral core into the cytoplasm. The viral core then traffics to the cell nucleus where it docks at the nuclear pore. Reverse transcription converts the viral RNA genome into double-stranded DNA, forming the pre-integration complex (PIC) that is imported into the nucleus. The viral genome is then integrated into the host cell chromosome. Prior to or during nuclear import, the capsid disassembles in a process termed uncoating. In a restriction-competent cell, TRIM5 intercepts and disables the core in a manner that induces failure of reverse transcription.
Figure 2 |
Figure 2 |. Structural and functional properties of TRIM5.
a | Schematics of the primary sequences of TRIM5α and TRIMCyp. These proteins share a common tripartite motif (TRIM, also known as RBCC motif), composed of RING, B-box 2 and coiled-coil domains. The RING and B-box 2 domains are connected by a flexible segment, Linker 1 (L1). Linker 2 (L2) connects the RBCC scaffold to the capsid-binding domains, SPRY in TRIM5α and CypA in TRIMCyp. b | The B-box 2 and coiled-coil domains make up the basal dimer scaffold structure of TRIM5 (PDB code 4TN3), and defines the spatial dispositions of the N-terminal RING and C-terminal capsid binding domains. c | The B-box 2 domain forms trimers (PDB code 5IEA) that can connect three dimers. The combination of coiled-coil mediated dimerization and B-box mediated trimerization generates a TRIM hexagonal lattice. d | The N-terminal RING domain dimerizes in order to bind a ubiquitin-conjugated E2 enzyme (PDB code 4TKP) and catalyze ubiquitination. c | In cells, TRIM5 undergoes higher-order assembly to form cytoplasmic bodies. These bodies can assemble spontaneously or form around an incoming retrovirus core.
Figure 3 |
Figure 3 |. Mechanism of core recognition by TRIM5.
a | In TRIM5α, the two SPRY domains are thought to function as a single unit to bind the assembled CA subunits on the capsid. The structure of the SPRY domain is known, (PDB code 2LM3), and binding requires the flexible V1 loop. However, it is not yet known precisely how the SPRY domain contacts CA. b | In TRIMCyp, the two CypA domains are connected flexibly to the TRIM scaffold and binds to cyclophilin-binding loops displayed on the surface of the HIV-1 capsid (PDB code 1AK4). c | Model of a TRIM-coated capsid, assembled from crystal structures of the HIV-1 CA hexamer (PDB code 3H47) and pentamer (PDB code 3P05), and rhesus TRIM5α coiled-coil dimer, B-box 2 trimer, and SPRY domain (PDB codes 3H47, 3P05, 4TN3, 5EIA, and 2LM3).
Figure 4 |
Figure 4 |. Mechanism of TRIM5-mediated restriction.
TRIM5 recognizes an incoming retrovirus core by binding to the capsid shell that coats and protects the core. The assembled TRIM5 proteins make a cage that surrounds and traps the core. a | Some studies indicate that binding of TRIM5 to the capsid is sufficient to induce premature and non-productive uncoating,,,,. This leads to failure of reverse transcription. b | Other studies indicate that accelerated core dissociation induced by TRIM5 requires ubiquitination and recruitment of proteasomes,,. Proteasome recruitment can also lead to virus clearance after the core has been inactivated. A very recent study shows that immunoproteasomes, a specific type of proteasome, allows HIV-1 restriction by human TRIM5α. c | Other studies invoke virus clearance through a mechanism of precision autophagy termed virophagy, in which TRIM5 directs the bound retrovirus core to isolation membranes and, eventually, lysosomes for degradation.
Figure 5 |
Figure 5 |. TRIM5-mediated signaling.
TRIM5 protein levels are normally kept low by rapid turnover, either through proteasomal or autophagosomal degradation. Cage formation around a restriction-susceptible capsid triggers production of K63-linked polyubiquitin chains, which activate interferon signaling through the AP1 and/or NF-kB pathways,. The signaling K63-linked polyubiquitin chains are reported to be either unanchored or attached to the TRIM5 N-terminus. Interferon induction is not required for virus inhibition in tissue culture systems, but likely contributes to effective virus control in vivo.

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