# Epigenomic Control of KSHV Latency

> **NIH NIH R01** · WISTAR INSTITUTE · 2024 · $410,175

## Abstract

Abstract:
Kaposi’s Sarcoma (KS)-Associated Herpesvirus (KSHV) is a human g-herpesvirus responsible for KS, pleural
effusion lymphoma (PEL), multlicentric Castleman’s disease (MCD) and KSHV inflammatory cytokine syndrome
(KICS). KS and PEL are HIV-AIDS-defining malignancies that occur at high frequency during AIDS, but also
after treatment with ART especially in endemic regions. KSHV oncogenesis is driven by the complex life cycle
of KSHV involving long-term latent infection of B-lymphocytes, reactivation and persistent infection of lymphatic
endothelial and mesenchymal stem cells, and immune evasion. KSHV encoded nuclear antigen LANA is
expressed in all KSHV-associated tumors and is essential for maintenance of the viral episome during latent
infection in proliferating cells. KSHV LANA is also thought to contribute directly to viral oncogenesis and
pathogenesis through interactions with tumor suppressor proteins and rewiring of host gene expression
programs. We have previously shown that LANA contributes to the viral DNA replication, epigenetic regulation
and higher-order structure of KSHV episomes. We have also identified chromatin organizing factors, such as
CTCF and cohesins, as key regulatory factors in the control of latent gene expression and restriction of lytic
reactivation. More recently, we have explored KS tumor transcriptomics and drug sensitivity assays to identify
metabolic pathways implicated in the regulation of LANA and KSHV-infected cell survival. We now propose to
advance each of these findings and continue our long-term effort to understand the role of LANA in episome
maintenance, latency regulation, and oncogenesis. Specifically, we will investigate (1) the role of LANA in
regulating latency-associated DNA replication and genome integrity through a potential intrinsic tyrosine
recombinase activity that regulates replication termination and genome decatenation at the viral terminal repeats,
(2) the role of LANA and cellular chromatin organizing factors DAXX, CTCF and cohesin in forming higher-order
nuclear bodies that protect and organize the viral episome to maintain stable genomes and gene expression
patterns in latently infected cells, and (3) how onco-metabolic stress disrupts LANA function and KSHV latency
to drive tumorigenesis. Together these studies provide an integrated framework to further advance our
knowledge of KSHV infection and latency, and provide new opportunities for therapeutic intervention in KSHV-
associated disease.

## Key facts

- **NIH application ID:** 10838618
- **Project number:** 5R01CA117830-17
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** PAUL M. LIEBERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,175
- **Award type:** 5
- **Project period:** 2006-04-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838618

## Citation

> US National Institutes of Health, RePORTER application 10838618, Epigenomic Control of KSHV Latency (5R01CA117830-17). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10838618. Licensed CC0.

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