# Cell model for KSHV Infection and Genetic Manipulation

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $391,250

## Abstract

Project Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), and several
other cancers. Despite intensive studies, the mechanism underlying KSHV-induced cellular transformation
remains unclear. This critical gap of knowledge has impeded the development of effective therapeutic
approaches. KSHV genome encodes over a dozen of proteins that regulate cell proliferation, growth and
survival; however, their roles in KSHV-induced oncogenesis have not been defined because of the lack of an
efficient model of cellular transformation of primary cells. In the current funding period, we have made
significant progresses toward this goal. We have discovered that KSHV can efficiently infect, immortalize and
transform primary rat and human mesenchymal precursor cells (MM). This breakthrough, for the first time, has
made it possible to delineate viral genes and cellular pathways required for KSHV-induced cellular
transformation and tumorigenesis. Using this novel model combining with a reverse genetic approach, we have
found that, in contrast to results of previous single gene expression studies, in the context KSHV infection viral
vCyclin (ORF72) is required for cell cycle progression and cell proliferation in contact-inhibited condition but not
in normal cell proliferative condition. Significantly, vCyclin promotes KSHV-induced cellular transformation and
tumorigenesis. Furthermore, we have recently developed a unique Crispr-Cas9 library, performed a preliminary
screening, and identified numerous cellular genes and pathways that are essential for KSHV-induced cellular
transformation. Based on these preliminary studies, we have formulated a working hypothesis that KSHV
induces cellular transformation and tumorigenesis by encoding specific viral genes to manipulate
essential cellular gene(s)/pathway(s). We will carry out two integrated and synergistic Specific Aims: (1) To
identify viral genes required for KSHV-induced cellular transformation and tumorigenesis, and define their
mechanisms of action; and (2) To delineate the mechanism by which vCyclin mediates KSHV-induced cellular
transformation and tumorigenesis. Upon completion of this project, our expectations are to identify the viral
essential genes required for KSHV-induced cellular transformation, and define the mechanisms of action with
focus on vCyclin. Together, these results will be highly significant and innovative because we will use a novel
KSHV transformation model of primary cells and a novel Crispr-Cas9 screening approach to delineate viral
oncogenes and cellular genes/pathways essential for cellular transformation. These studies will provide
insights into the oncogenesis of KSHV-induced cancers and possibly other cancers, and identify novel targets
for developing innovative therapeutic approaches for KSHV-induced malignancies.

## Key facts

- **NIH application ID:** 9868255
- **Project number:** 5R01CA096512-14
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Shou-Jiang Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2003-01-13 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9868255

## Citation

> US National Institutes of Health, RePORTER application 9868255, Cell model for KSHV Infection and Genetic Manipulation (5R01CA096512-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9868255. Licensed CC0.

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