Kinases from HIV-1 Infected Exosomes Drive Cell Cycle Progression in Recipient Cells

Abstract

Human immunodeficiency virus type 1 (HIV-1) is a retrovirus that depletes CD4+ cells and progresses into acquired immunodeficiency syndrome (AIDS) if left untreated [1]. As of 2022, HIV-1 caused around 88.4 million infections and 42.3 million deaths [2]. Currently, combination antiretroviral therapy (cART) is an effective therapeutic, which prevents AIDS by blocking various stages of the HIV-1 life cycle; however, it is not a cure, as low levels of viral production persist in cART patients [3]. This is partially due to exosomes, which are membrane-bound vesicles that transport proteins and nucleic acids between cells for communication [4]. When infected, exosomes carry viral and host materials that instigate infection, such as exosome-associated host kinases CDK10, GSK-3B, and MAPK8 [4, 5]. In this study, we examined how the kinases influence cell cycle progression, a key aspect of HIV-1 pathogenesis. Exosomes were isolated from infectious ACH2 and U1 cells, treated with kinase-suppressing drugs, and administered to U937 and CEM cells in G0. Levels of cell cycle proteins were then assessed through western blot to determine cycle status. Cyclins D and E, which engage in G1/S transition, decreased in CEM cells treated with ACH2 exosomes on CDK10-inhibiting NVP2, suggesting inhibition causes G1 arrest. Conversely, Cyclin E and CDK2 increased in U937 cells treated with U1 exosomes on GSK-3B-inhibiting AZD2858 and MAPK8-inhibiting DB07268, indicating inhibition allows for G1/S progression. These findings enhance our understanding of host protein impact in HIV-1 proliferation and can be considered in the development of novel therapies.

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