Dissertation
HIV-1 Tat activates ERK1/2 signaling in HBV-infected hepatocytes to inhibit HBV replication and promote hepatocyte survival
Doctor of Philosophy (Ph.D.), Drexel University
Jan 2025
DOI:
https://doi.org/10.17918/00010807
Abstract
Globally, a chronic hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC). The increased risk of HCC persists in patients treated with antiviral therapy, despite suppressing viral replication. Co-infection with human immunodeficiency virus (HIV) increases the risk of developing HCC by 18-fold relative to an HBV mono-infection. Despite the clear clinical burden posed by an HIV/HBV co-infection, the mechanisms underlying the increased risk of HCC are understudied due to a lack of relevant model systems. We developed an in vitro model of HIV/HBV co-infection using Jurkat cells with inducible expression of HIV-1 Tat co-cultured with HBV-infected primary rat hepatocytes. The co-culture model was used to investigate the effect of HIV-1 Tat on HBV replication and cell survival in HBV-infected hepatocytes. Results from Jurkat-secreted Tat were complemented with purified HIV-1 Tat to determine the effect of Tat alone. Exposure to Tat significantly upregulated ERK1/2 and NF-[kappa]B signaling and cell survival in HBV-infected and uninfected hepatocytes. The activation of ERK1/2 and NF-[kappa]B signaling by Tat also inhibited HBV replication, which could be rescued by inhibition of ERK1/2 with temuterkib. Tat-dependent activation of NF-[kappa]B signaling and cell survival was also reversed by treatment with temuterkib. Tat-mediated activation of NF-[kappa]B signaling and cell survival is initiated by the TLR-4 cell surface receptor and recruitment of PKC-delta to the plasma membrane. Overall, the results of these studies indicate that Tat-mediated upregulation of ERK1/2 may promote oncogenesis and contribute to the development of HCC during an HIV/HBV co-infection by promoting cell survival.
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Details
- Title
- HIV-1 Tat activates ERK1/2 signaling in HBV-infected hepatocytes to inhibit HBV replication and promote hepatocyte survival
- Creators
- Kyle Christopher Yeakle
- Contributors
- Michael R. Nonnemacher (Advisor)Michael Bouchard (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- viii, ii, 108 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991022019918104721