Unraveling the molecular link between HIVAIDS and cancer

Division Of Basic Sciences - Nci

Investigators

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Abstract

Our unbiased proteomic mass spectrometry and subsequent biochemical analyses showed that Plk4 binds to the C-terminal acidic domain (1401-1507) of a cellular scaffold protein, VprBP, via its C-terminal cryptic polo-box. Strikingly, HIV-1 Vpr, which binds to the WD40 domain (1003-1400) of VprBP, greatly enhanced the VprBP-Plk4 interaction and induced the formation of the Vpr-VprBP-Plk4 complex. All three proteins colocalized to centrosomes and the formation of the ternary complex appeared to augment Plk4-mediated centriole duplication. Consistent with these findings, VprBP promoted Plk4 function by stabilizing its centriole-associated state rather than inducing its proteasomal degradation, as was observed for the Vpx-VprBP-SAMHD1 complex and other cellular targets. These data suggest that, when cells are infected with HIV-1, Vpr may alter Plk4's function by forming the Vpr-VprBP-Plk4 complex under physiological conditions and induce Plk4-dependent centriole overduplication, a cellular event causing aneuploidy and cancer. A structurally related HIV-2 Vpx failed to interact with VprBP and Plk4, indicating the specificity of HIV-1 Vpr-induced events. Based on these observations, we postulate that HIV-1 Vpr can directly alter genomic stability and facilitate carcinogenesis by hijacking the cellular Plk4-VprBP complex. Additional studies are planned to determine the role of the ternary Vpr-VprBP-Plk4 complex under physiologically relevant conditions, using HIV-1-susceptible cells and tissues in animal models. This research could shed light on the mechanism that could directly link HIV/AIDS to the etiology of its comorbid cancers. Furthermore, it may offer a new paradigm in understanding the increased cancer risk in people living with HIV-1. Investigating HIV-induced comorbidities is one of the four designated NIH HIV/AIDS research priorities. This research is designed to directly address HIV-1-associated cancer comorbidities. We have gained an enriched experience in studying how HIV proteins interact with cellular targets and alter cell physiology using various biochemical and structure-based analyses. Investigation into the way in which SARS-CoV-2 (COVID-19) recognizes its human cell surface receptor and isolation of small molecular inhibitors that disrupt this event would be critical for the intervention of viral entry into host cells. The exceptional high-affinity interaction between the COVID-19 spike protein (S protein) and the human extracellular receptor, ACE2, underlies the widespread pandemic of COVID-19. We are seeking to establish a specific COVID-19 S protein-ACE2 interaction trap using a membrane protein-friendly lipid-bilayer platform to isolate and develop small molecule inhibitors against COVID-19 entry into host cells.