# KSHV Latent Infection Replication

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $633,853

## Abstract

Abstract
 Kaposi's sarcoma (KS) herpesvirus (KSHV) is the etiologic agent of KS, primary effusion lymphoma
(PEL), and multicentric Castleman's disease (MCD). These tumors occur most commonly in individuals with
AIDS or other immunocompromising conditions. Currently, there are no specific therapies for these diseases.
KS is the leading AIDS malignancy, and is epidemic throughout sub Saharan Africa. KS commonly involves the
oral cavity and can widely disseminate to visceral organs. Saliva is the vehicle of transmission for KSHV.
 Following infection, epigenetic modifications associated with transcriptional activation are deposited on
the KSHV genome, leading to widespread, but brief, viral gene expression. Failure to inhibit this expression
leads to lytic replication. Repressive H2AK119ub and H3K27me3 modifications subsequently accumulate to
silence lytic gene promoters. H2AK119ub accrues initially, followed by H3K27me3, in contrast to the classical
model in which H3K27me3 marks precede H2AK119ub.
 Latency is the hallmark of KSHV and gammaherpesvirus infection. KSHV latently infects cells, including
tumor cells, and viral genomes persist as circular, extrachromosomal, multi-copy, episomes. To persist in
proliferating cells, viral episomes must replicate, and subsequently, segregate to daughter nuclei. Tumor cell
viability is dependent on latent KSHV infection.
 The latency-associated nuclear antigen (LANA) is one of a limited number of virus genes expressed in
latency. LANA is responsible for KSHV episome maintenance and is necessary and sufficient for virus episome
persistence in the absence of other viral genes. In addition to episome persistence, LANA exerts important
roles in transcriptional regulation and growth control. LANA is involved in silencing the viral genome.
 We have discovered LANA interacts with a component of the DNA damage response (DDR), and that
the DDR silences the viral genome following infection, thereby inhibiting lytic replication and allowing latency
establishment. This work will use rigorous, detailed, in depth approaches to investigate the mechanistic basis
of these findings. Experiments will investigate the LANA-DDR interaction and its role in viral genome silencing,
and suppression of lytic replication. We will investigate the dynamics and sites of deposition of key DDR
factors on the KSHV genome and LANA’s role in these events. Experiments will also investigate the role of the
DDR in establishing the KSHV repressive epigenome. The silencing of the KSHV genome following infection is
central to the establishment of viral latency, and this work therefore provides novel and important insight into a
fundamental component of KSHV biology.

## Key facts

- **NIH application ID:** 10271003
- **Project number:** 2R01DE025208-06A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Kenneth M Kaye
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $633,853
- **Award type:** 2
- **Project period:** 2015-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10271003

## Citation

> US National Institutes of Health, RePORTER application 10271003, KSHV Latent Infection Replication (2R01DE025208-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10271003. Licensed CC0.

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