# Defining mechanisms of KSHV pathogenesis using MHV68-KSHV chimeric viruses

> **NIH NIH R56** · UNIV OF ARKANSAS FOR MED SCIS · 2020 · $525,786

## Abstract

PROJECT SUMMARY
Gammaherpesviruses (GHVs) are DNA tumor viruses that establish lifelong, chronic infections of host
lymphocytes. The expression of viral gene products that manipulate host cell physiology and thwart antiviral
immune responses places the infected host at risk for numerous cancers. For individuals with AIDS, infection by
Kaposi sarcoma-associated herpesvirus (KSHV) is a major cause of morbidity and mortality. However, KSHV
does not readily infect mice, which complicates attempts to define mechanisms by which KSHV establishes long-
term infections and disease. To overcome this barrier, we have used a chimeric virus approach in which KSHV
genes are transferred into the closely related virus, murine gammaherpesvirus 68 (MHV68), which is a natural
rodent pathogen that readily infects laboratory mice. We used this MHV68-KSHV chimeric virus approach to
evaluate the KSHV latency-associated nuclear antigen (kLANA) during productive viral replication, latency
establishment, and maintenance. We found that kLANA was sufficient to replace MHV68 LANA (mLANA) for
viral latency. However, kLANA, but not mLANA, suppressed MHV68 lytic replication by inhibiting the activity of
the promoter for lytic transactivator RTA. Our work demonstrates that chimeric viruses offer opportunities for
dissecting functions of KSHV proteins in a living host, and that this system can define evolutionarily acquired
features of a viral oncoprotein. Experiments described in this proposal will further define functions of KSHV LANA
in viral pathogenesis and evolutionary divergence from mLANA. We will use the repressed lytic replication of the
kLANA-expressing chimeric virus to define how the amplitude of lytic replication influences immunity to infection
and oncogenic potential of the virus. Finally, we will extend our chimeric virus studies with LANA, dovetailing
them with MHV68-KSHV chimeric viruses for v-Cyclin and v-GPCR, to develop the next generation of chimeras
in which multiple MHV68 genes are replaced with their KSHV counterparts. Through this work we will improve
small animal models to enable molecular mechanistic studies of KSHV oncoproteins in viral infection and disease
and provide a preclinical testing platform to foster the development of therapies that target LANA and other viral
proteins to treat or prevent KSHV-related cancers.

## Key facts

- **NIH application ID:** 10243300
- **Project number:** 1R56AI150911-01A1
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** James Craig Forrest
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $525,786
- **Award type:** 1
- **Project period:** 2020-09-14 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10243300

## Citation

> US National Institutes of Health, RePORTER application 10243300, Defining mechanisms of KSHV pathogenesis using MHV68-KSHV chimeric viruses (1R56AI150911-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10243300. Licensed CC0.

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