# KSHV Latency Regulation

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2022 · $711,722

## Abstract

Kaposi's sarcoma (KS) herpesvirus (KSHV) is the causative agent of KS and primary effusion
lymphoma (PEL), and is tightly linked with multicentric Castleman's disease (MCD). These tumors occur most
commonly in immunocompromised individuals, especially those with AIDS. There are no specific therapies for
these malignancies. KS is the leading AIDS malignancy, and is epidemic in sub Saharan Africa. KS commonly
involves the oral cavity and can disseminate to visceral organs. Saliva is the vehicle of transmission for KSHV.
 Latency is the hallmark of KSHV and gammaherpesvirus infection. KSHV latently infects cells, including
tumor cells, and viral genomes persist as extrachromosomal, circularized, multi-copy, episomes. To persist in
proliferating cells, viral episomes must replicate, and following mitosis, segregate to daughter cell nuclei.
Tumor cell viability is dependent on latent KSHV infection.
 The latency-associated nuclear antigen (LANA) is one of several viral genes expressed in latency.
LANA mediates KSHV episome maintenance, and is necessary and sufficient for episome persistence in the
absence of other viral genes. In addition to episome persistence, LANA exerts important roles in transcriptional
regulation.
 Epigenetic histone H3 lysine 4 (H3K4) tri-methylation (H3K4me3) marks are associated with actively
transcribed genes and are deposited by histone methyltransferase (HMT) complexes. There are six HMTs
(MLL1-4, Set1A/B) in mammals responsible for catalyzing methylation of histone H3 at K4 through a SET
domain. LANA is highly enriched at H3K4me3 peaks at both viral and host chromatin, yet the mechanism of
LANA recruitment to and its function at these sites remains unclear.
 We have discovered novel LANA interactions with HMT components and that LANA regulates specific
HMT activity. Further, we find this HMT activity is critical for virus latency establishment. This work will use
rigorous, detailed, in depth approaches to investigate the mechanistic basis of these findings. Experiments will
investigate the role of the HMT activity in LANA mediated episome persistence. We will investigate the role of
the LANA-HMT interaction in LANA and HMT chromatin targeting of virus and host, and its effects on
H3K4me3 deposition and gene expression. Experiments will also investigate the mechanism of LANA’s
regulation of HMT activity and its role in virus latency. LANA and HMT activity are critical for latency, and this
work therefore provides novel and important insight into a fundamental component of KSHV biology.

## Key facts

- **NIH application ID:** 10412663
- **Project number:** 1R01AI165382-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Kenneth M Kaye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $711,722
- **Award type:** 1
- **Project period:** 2021-11-05 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412663

## Citation

> US National Institutes of Health, RePORTER application 10412663, KSHV Latency Regulation (1R01AI165382-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10412663. Licensed CC0.

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