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

Jung-Eun Park, Tae-Sung Kim, Yan Zeng, Melissa Mikolaj, Jong Ahn, Muhammad S. Alam, Christina M. Monnie, Victoria Shi, Ming Zhou, Tae-Wook Chun, Frank Maldarelli, Kedar Narayan, Jinwoo Ahn, Jonathan D. Ashwell, Klaus Strebel and Kyung S. Lee ()
Additional contact information
Jung-Eun Park: National Institutes of Health
Tae-Sung Kim: National Institutes of Health
Yan Zeng: National Institutes of Health
Melissa Mikolaj: National Institutes of Health
Jong Ahn: National Institutes of Health
Muhammad S. Alam: National Institutes of Health
Christina M. Monnie: University of Pittsburgh School of Medicine
Victoria Shi: National Institutes of Health
Ming Zhou: Frederick National Laboratory for Cancer Research
Tae-Wook Chun: National Institutes of Health
Frank Maldarelli: National Institutes of Health
Kedar Narayan: National Institutes of Health
Jinwoo Ahn: University of Pittsburgh School of Medicine
Jonathan D. Ashwell: National Institutes of Health
Klaus Strebel: National Institutes of Health
Kyung S. Lee: National Institutes of Health

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46306-8

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