Unraveling the molecular link between HIVAIDS and cancer

Division Of Basic Sciences - Nci

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Abstract

We discovered that approximately 1-5% of CD4+ T cells from the blood of cancer-free people living with HIV-1 exhibited over-duplicated centrioles. Thus, we hypothesize that HIV-1-induced centrosome amplification could play a role in developing HIV-1-associated comorbid cancers by promoting aneuploidy. To investigate the mechanism underlying this event, we performed affinity purification-mass spectrometry, biochemical, and cell biology analyses. The results showed that an HIV-1 accessory protein, Vpr, cooperatively generates a 1:1:2 ternary complex with its two cellular targets, VprBP and Plk4. The formation of the complex was detectable less than a minute after mixing three purified proteins in vitro. Furthermore, HIV-1 expressing Vpr WT but not a Plk4 binding-defective Vpr C-terminal deletion (deltaCT; lacking the residues 80-96) mutant (see below) induced centrosome amplification and aneuploidy in primary CD4+ T cells purified from the PBMCs of healthy human subjects (Park, JE et al., Nat Commun 2024). Based on these data, we propose to investigate further whether the Vpr-VprBP-Plk4 complex has the capacity to induce tumorigenesis. These data could offer unexpected insights into how comorbid cancers can arise in people living with HIV-1. This new research direction could yield further clues for understanding the mechanism of inducing HIV-1-associated cancers.