PML/TRIM19-Dependent Inhibition of Retroviral Reverse-Transcription by Daxx.

Jacques Dutrieux,Nathalie J Arhel,Mounira K Chelbi-Alix,Sébastien Nisole,Ghizlane Maarifi,Débora M Portilho,Christopher Aiken

doi:10.1371/journal.ppat.1005280

Jacques Dutrieux, Nathalie J Arhel + Show 5 more

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https://doi.org/10.1371/journal.ppat.1005280

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Abstract

PML (Promyelocytic Leukemia protein), also known as TRIM19, belongs to the family of tripartite motif (TRIM) proteins. PML is mainly expressed in the nucleus, where it forms dynamic structures known as PML nuclear bodies that recruit many other proteins, such as Sp100 and Daxx. While the role of PML/TRIM19 in antiviral defense is well documented, its effect on HIV-1 infection remains unclear. Here we show that infection by HIV-1 and other retroviruses triggers the formation of PML cytoplasmic bodies, as early as 30 minutes post-infection. Quantification of the number and size of PML cytoplasmic bodies revealed that they last approximately 8 h, with a peak at 2 h post-infection. PML re-localization is blocked by reverse-transcription inhibitors and is not observed following infection with unrelated viruses, suggesting it is specifically triggered by retroviral reverse-transcription. Furthermore, we show that PML interferes with an early step of retroviral infection since PML knockdown dramatically increases reverse-transcription efficiency. We demonstrate that PML does not inhibit directly retroviral infection but acts through the stabilization of one of its well-characterized partners, Daxx. In the presence of PML, cytoplasmic Daxx is found in the vicinity of incoming HIV-1 capsids and inhibits reverse-transcription. Interestingly, Daxx not only interferes with exogenous retroviral infections but can also inhibit retrotransposition of endogenous retroviruses, thus identifying Daxx as a broad cellular inhibitor of reverse-transcription. Altogether, these findings unravel a novel antiviral function for PML and PML nuclear body-associated protein Daxx.

Highlights

Intrinsic immunity constitutes the first line of defense against viral infection, as it relies on cellular proteins, known as restriction factors, to directly counteract viral replication
Among the several protection mechanisms raised by mammalian organisms against viral infections, an early line of defense consists of cellular proteins known as restriction factors that interfere with viral replication
We show that PML is rapidly re-localized in the cytoplasm of cells infected by HIV-1 and other retroviruses and interferes with reverse-transcription of incoming retroviral RNA

Summary

Introduction

Intrinsic immunity constitutes the first line of defense against viral infection, as it relies on cellular proteins, known as restriction factors, to directly counteract viral replication. Among the 70 members identified in human cells, TRIM5α is not the only TRIM protein with the capacity to interfere with HIV-1 replication [7,8,9,10]. Unlike TRIM5α whose antiviral activity only targets retroviruses, TRIM22 confers resistance to hepatitis B virus (HBV) [11], Encephalomyocarditis virus (EMCV) [12] and Influenza A virus [13]. Another TRIM protein that displays a broad intrinsic antiviral activity is TRIM19, better known as PML, for Promyelocytic Leukemia protein. Many viruses have developed strategies to counteract PML NB repression by disrupting PML NBs and/or by inducing PML degradation [27,28]

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