TRIM34 restricts HIV-1 and SIV capsids in a TRIM5α-dependent manner.

Molly Ohainle,Jeremy Luban,Kyusik Kim,Abby Felton,Sevnur Komurlu Keceli,Ed Campbell,Michael Emerman,David T Evans

doi:10.1371/journal.ppat.1008507

Abstract

The HIV-1 capsid protein makes up the core of the virion and plays a critical role in early steps of HIV replication. Due to its exposure in the cytoplasm after entry, HIV capsid is a target for host cell factors that act directly to block infection such as TRIM5α and MxB. Several host proteins also play a role in facilitating infection, including in the protection of HIV-1 capsid from recognition by host cell restriction factors. Through an unbiased screening approach, called HIV-CRISPR, we show that the CPSF6-binding deficient, N74D HIV-1 capsid mutant is sensitive to restriction mediated by human TRIM34, a close paralog of the well-characterized HIV restriction factor TRIM5α. This restriction occurs at the step of reverse transcription, is independent of interferon stimulation, and limits HIV-1 infection in key target cells of HIV infection including CD4+ T cells and monocyte-derived dendritic cells. TRIM34 can also restrict some SIV capsids. TRIM34 restriction requires TRIM5α as knockout or knockdown of TRIM5α results in a loss of antiviral activity. Through immunofluorescence studies, we show that TRIM34 and TRIM5α colocalize to cytoplasmic bodies and are more frequently observed to be associated with infecting N74D capsids than with WT HIV-1 capsids. Our results identify TRIM34 as an HIV-1 CA-targeting restriction factor and highlight the potential role for heteromultimeric TRIM interactions in contributing to restriction of HIV-1 infection in human cells.

Highlights

The HIV-1 capsid protein (CA or p24gag) forms the core of the virion and is key to effective delivery of the HIV-1 genome inside a host cell and into the nucleus where integration into the host chromosome occurs [1, 2]
Through an unbiased screening approach, called HIV-CRISPR, we show that the CPSF6-binding deficient, N74D HIV-1 capsid mutant is sensitive to restriction mediated by human TRIM34, a close paralog of the wellcharacterized HIV restriction factor TRIM5α
We show that TRIM34 and TRIM5α colocalize to cytoplasmic bodies and are more frequently observed to be associated with infecting N74D capsids than with wild type (WT) HIV-1 capsids

Summary

Introduction

The HIV-1 capsid protein (CA or p24gag) forms the core of the virion and is key to effective delivery of the HIV-1 genome inside a host cell and into the nucleus where integration into the host chromosome occurs [1, 2]. Human TRIM5α, previously thought to lack significant activity against primate lentiviruses, has recently been shown to restrict wild type (WT) HIV-1 capsids in IFN-treated cells [6, 7]. While the affinity of the SPRY domain for CA is low, this low affinity is overcome by TRIM5α dimerization and its ability to form higher-order assemblies around the viral core, enhancing avidity of the TRIM5α-CA interaction [8]. One key aspect of TRIM biology that remains relatively unexplored includes the potential for hetero-oligomerization of TRIM proteins that could have important functional consequences

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Discussion

Conclusion