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TRIM34 restricts HIV-1 and SIV capsids in a TRIM5α-dependent manner
Molly Ohainle1, Kyusik Kim2, Sevnur Komurlu Keceli3
1Divisions of Human Biology and Basic Sciences, Fred Hutch, Seattle, Washington, United States of America.
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.
Insights
Human TRIM34 protein restricts human immunodeficiency virus type 1 (HIV-1) infection by targeting the viral capsid. This TRIM34 restriction requires TRIM5α and impacts HIV-1 replication in immune cells.
Area of Science:
- Virology
- Immunology
- Molecular Biology
Background:
- The human immunodeficiency virus type 1 (HIV-1) capsid protein is crucial for viral replication and is exposed to host cell restriction factors in the cytoplasm.
- Host proteins can either block or facilitate HIV-1 infection by interacting with the viral capsid.
- TRIM5α is a known HIV-1 restriction factor, and its paralog, TRIM34, is investigated here.
Purpose of the Study:
- To identify novel host factors that restrict HIV-1 infection.
- To investigate the role of TRIM34 in HIV-1 restriction.
- To understand the mechanism of TRIM34-mediated restriction.
Main Methods:
- Employed an unbiased HIV-CRISPR screening approach to identify host restriction factors.
- Utilized a CPSF6-binding deficient N74D HIV-1 capsid mutant for sensitivity assays.
- Performed immunofluorescence studies to examine protein colocalization and association with viral capsids.
Main Results:
- Identified human TRIM34 as a novel restriction factor targeting the HIV-1 capsid.
- TRIM34 restriction of the N74D HIV-1 capsid mutant occurs during reverse transcription and is independent of interferon.
- TRIM34 restriction necessitates TRIM5α, as TRIM5α knockout/knockdown abrogates TRIM34's antiviral activity, and both proteins colocalize with N74D capsids.
Conclusions:
- TRIM34 acts as an HIV-1 capsid-targeting restriction factor in human cells.
- TRIM34 restriction is dependent on TRIM5α, suggesting a role for heteromultimeric TRIM interactions in antiviral defense.
- This study expands our understanding of host-virus interactions and potential therapeutic targets against HIV-1.
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