# KSHV immortalization of human lymphatic endothelial cells

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $428,374

## Abstract

Abstract:
Opportunistic infections are a major cause of morbidity and mortality of AIDS patients in developing countries
and AIDS patients are susceptible to a number of cancers caused by opportunistic infections. Kaposi's Sarcoma
(KS) is the most common tumor of AIDS patients and is the among the most commonly reported tumor overall
in countries in sub-Saharan Africa, where it commonly occurs in both HIV+ and HIV- people. The etiologic
agent of KS is Kaposi's Sarcoma-associated herpesvirus (KSHV or HHV-8). KSHV is invariably found in the
main KS tumor cell, the spindle cell, where the virus is present predominantly in the latent state. Spindle cells
express markers of lymphatic endothelial cells and appear to be most closely aligned with this cell type. While
KSHV is clearly an oncogenic virus, little is known about the early steps of how KSHV infection of endothelial
cells leads to tumors. While there have been studies that have examined KSHV Induced immortalization and
transformation, there is a lack of tractable and reproducible relevant human cell system. We found that KSHV
infection of primary neonatal lymphatic endothelial cells (LECs) leads to bypass of senescence, the first step in
immortalization. We also demonstrated that the viral Cyclin homolog (vCyc) was essential for KSHV driven
proliferation past senescence. KSHV infected neonatal blood endothelial cells (BECs) senesced at the same
passage as uninfected blood or lymphatic endothelial cells indicating this phenotype is LEC specific. There is
not a strong interferon response in LECs following KSHV infection. In preliminary data we found that
knockout of STING in the BECs, preventing the IFN response, made them susceptible to KSHV induced
proliferation past senescence, indicating that STING or STING activated pathways prevent KSHV induced
proliferation past senescence. In this proposal we will determine if STING expression is sufficient for this
phenotype and the mechanism of STING inhibition of KSHV induced proliferation past senescence. We will
also determine the mechanism of vCyc activation of endothelial cells to proliferate past senescence. These data
provide a robust system for analyzing the mechanism of how KSHV drives the first step of oncogenesis in
endothelial cells and why it is specific to LECs. We will further study KSHV induced oncogenesis in our new
endothelial precursor cell (EPC) model. We previously found that EPCs isolated from human blood could be
separated into lymphatic like EPCs and blood like EPCs. We found that the Ly-EPCs were able to proliferate to
low levels in soft agar but uninfected Ly-EPCs and uninfected or KSHV infected Bl-EPCs could not. This
presents a second oncogenic assay for studying how KSHV activates cell proliferation in lymphatic endothelial
cells but not blood. Ultimately, the proposed studies will help identify how KSHV alters endothelial cells to
become cancer cells and ultimately KS tumors and help in the identification of novel therapeu...

## Key facts

- **NIH application ID:** 10917945
- **Project number:** 2R01CA217788-06A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Michael Lagunoff
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $428,374
- **Award type:** 2
- **Project period:** 2018-02-12 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10917945

## Citation

> US National Institutes of Health, RePORTER application 10917945, KSHV immortalization of human lymphatic endothelial cells (2R01CA217788-06A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10917945. Licensed CC0.

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