Abstract
BACKGROUND: Human immunodeficiency viruses (HIV-1 and HIV-2), are the causative agents of the acquired immunodeficiency syndrome (AIDS), that share substantial genomic and structural similarities, yet differ in replication dynamics and disease progression. While HIV-1 primarily enters host cells via CD4 and the chemokine co-receptors CCR5 and CXCR4, HIV-2 engages a broader range of chemokine receptors. The transferrin receptor (TFRC/CD71), a membrane protein essential for iron uptake and immune function, has recently been implicated in viral entry by other pathogens. In this study, we investigated the modulation of TFRC expression following transduction with HIV-1 and HIV-2 pseudovirions. METHODS: Human embryonic kidney (HEK-293T), immortalized T lymphocyte (Jurkat), and monocytic (THP-1) cells were transduced with pseudotyped HIV-1 and HIV-2 virions. Quantitative PCR (qPCR) and western blotting were employed to assess changes in TFRC expression at the mRNA and protein levels, respectively. To elucidate the underlying mechanism, we examined the role of the HIV-2 regulatory protein Tat in TFRC modulation. Additionally, we assessed whether TFRC upregulation correlates with increased iron uptake during the early phase of infection. RESULTS: We observed a significant upregulation of TFRC mRNA and protein levels in HEK-293T cells 27 h post-transduction with HIV-2, but not with HIV-1. In Jurkat T cells, TFRC transcript levels were significantly increased at 36 and 40 h following HIV-2 transduction. At the proteomic level, TFRC abundance was modestly reduced in HIV-2-transduced cells at 36 and 48 h, suggesting a potential compensatory cellular response. In THP-1 cells, HIV-2 induced a significant downregulation of TFRC at both the transcriptomic and proteomic levels at 36 h. Mechanistic studies demonstrated that this modulation is likely dependent on a functional HIV-2 Tat protein. Furthermore, HIV-2 transduction led to elevated intracellular iron levels in Jurkat cells at 48 h post-transduction. CONCLUSION: These findings identify TFRC as a novel, Tat-dependent host target of HIV-2, providing new insights into the virus's broader receptor usage and its potential influence on host iron metabolism and viral tropism.