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Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4⁺ T cells.

ABSTRACT: HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4⁺ T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4⁺ T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.

SUBMITTER: Park JE

PROVIDER: S-EPMC10914751 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4<sup>+</sup> T cells.

Park Jung-Eun JE Kim Tae-Sung TS Zeng Yan Y Mikolaj Melissa M Il Ahn Jong J Alam Muhammad S MS Monnie Christina M CM Shi Victoria V Zhou Ming M Chun Tae-Wook TW Maldarelli Frank F Narayan Kedar K Ahn Jinwoo J Ashwell Jonathan D JD Strebel Klaus K Lee Kyung S KS

Nature communications 20240305 1

HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4<sup>+</sup> T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, ...[more]

PMID: 38443376

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Project description:The interactions between a virus and its host are complex but can be broadly categorized as either viral manipulation of cellular functions or cellular responses to infection. These processes begin at the earliest point of contact between virus and cell and frequently result in changes to cellular gene expression, making genome-wide transcriptomics a useful tool to study them. Several previous studies have used transcriptomics to evaluate the cellular responses to human immunodeficiency virus type 1 (HIV-1) infection; however, none have examined events in primary CD4+ T cells during the first 24 h of infection. Here, we analyzed CD4+ T cells at 4.5, 8, 12, 24, and 48 h following infection. We describe global changes to host gene expression commencing at 4.5 h postinfection and evolving over the ensuing time points. We identify upregulation of genes related to innate immunity, cytokine production, and apoptosis and downregulation of those involved in transcription and translation. We further demonstrate that the viral accessory protein Vpr is necessary for almost all gene expression changes seen at 12 h postinfection and the majority of those seen at 48 h. Identifying this new role for Vpr not only provides fresh perspective on its possible function but also adds further insight into the interplay between HIV-1 and its host at the cellular level. IMPORTANCE HIV-1, while now treatable, remains an important human pathogen causing significant morbidity and mortality globally. The virus predominantly infects CD4+ T cells and, if not treated with medication, ultimately causes their depletion, resulting in AIDS and death. Further refining our understanding of the interaction between HIV-1 and these cells has the potential to inform further therapeutic development. Previous studies have used transcriptomics to assess gene expression changes in CD4+ T cells following HIV-1 infection; here, we provide a detailed examination of changes occurring in the first 24 h of infection. Importantly, we define the viral protein Vpr as essential for the changes observed at this early stage. This finding has significance for understanding the role of Vpr in infection and pathogenesis and also for interpreting previous transcriptomic analyses of HIV-1 infection.

Dataset Information

Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4⁺ T cells.

Publications

Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4<sup>+</sup> T cells.

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Dataset Information

Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells.

Publications

Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4<sup>+</sup> T cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Centrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4⁺ T cells.