The KSHV genome, devoid of the essential immediate early transactivator RTAORF50, induces angiosarcoma in transgenic mice

Kaposi Sarcoma-associated herpesvirus (KSHV) extensively alters host cell signaling to induce a variety of malignant and premalignant phenotypes, including Kaposi sarcoma (KS). The mechanisms by which KSHV initially induces KS remain unclear due to a lack of animal models, as the human pathogen KSHV does not productively infect rodents or non-human primates. Our lab has recently developed a small-animal model of KS by integrating the entire 160-kb KSHV viral genome into the germline of mice, thereby circumventing rodent barriers to viral replication. KSHV transgenic mice develop a murine angiosarcoma indistinguishable from human KS by histology and transcriptional profile; however, deletion of the viral miRNA locus was required for the transgene founder animals to produce offspring. This yielded the FVBNJ-Tg(HHV8)197DtmrMmnc line (Cell Host Microbe. 2024 32(5):755-767). We have now generated another KSHV transgenic mouse line that carries all viral miRNAs but lacks the immediate-early transactivator RTA/ORF50, which is necessary and sufficient to induce lytic gene transcription. Without RTA/ORF50, the viral miRNAs are compatible with embryonic development. The intact transgene is transmitted in Mendelian fashion, and homozygous animals are viable. The Tg(HHV8dRta) mice have significantly higher overall survival but still develop angiosarcoma. The dispensability of RTA for murine KS has significant implications for the role of viral replication in KSHV oncogenesis. Pending further studies, we hypothesize that RTA-dependent genes are not required for tumor formation. Alternatively, transcripts that are classified as strictly lytic in other herpesviruses may have alternative modes of regulation in KSHV. Tumor cell lines derived from HHV8dRta murine KS tumors grow indefinitely in culture, providing a powerful new tool for KSHV research. A detailed comparison of tumor biology in KSHV transgenic mice with or without the essential immediate early transactivator will be presented.