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NIH grant 1R01DE035802-01A1: The transactivation of human endogenous retrovirus (HERV)-K by oncogenic virus in HIV+ patients and development of targeted therapies
Institute: {'code': 'DE', 'abbreviation': 'NIDCR', 'name': 'National Institute of Dental and Craniofacial Research', 'admin_org_id': '12500070', 'admin_funding_url': ''}. PI: Zhiqiang Qin. Award: $647465.
Start: 2026-08-28T00:00:00.
Abstract
Kaposi’s Sarcoma-associated Herpesvirus (KSHV) is the etiologic agent of several human cancers, including
Kaposi’s Sarcoma (KS) and Primary Effusion Lymphoma (PEL), which preferentially arise in
immunocompromised patients and lack of effective therapeutic options. KS also represents one of common
oral cancers in these patients. Human Endogenous Retrovirus Sequences (HERVs) constitute up to 8% of the
human genome, yet not all HERVs remain silent passengers within our genomes. Some HERVs, especially the
HERV type K (HERV-K), have been found to be frequently transactivated in patients with immunodeficiency,
and in a variety of inflammatory diseases and human cancers. However, the role of HERV-K transactivation in
viral oncogenesis, especially KSHV-induced tumorigenesis, remains almost unknown. Our preliminary data
indicate that either KSHV de novo infection or ectopic expression of KSHV-encoded major latent protein, LANA,
effectively transactivate HERV-K from both host primary and tumor cells. We found higher levels of HERV-K
transactivation in the PBMCs from cohort HIV+ patients with KSHV coinfection. There is a strong expression of
HERV-K-encoded oncoprotein, Np9, within AIDS-KS tissues. Further functional assays indicate that HERV-K
transactivation or activation of HERV-K Np9 expression is responsible for enhancing cell invasiveness,
anchorage-independent growth of KSHV+ cells and KSHV-induced DNA damage response (DDR). In addition,
HERV-K transactivation is related to the chemoresistance of KSHV+ lymphoma cells. Based on these data,
we hypothesize that transactivation of HERV-K may act as an important cofactor required for KSHV
pathogenesis and the development of virus-related malignant transformation, while targeting HERV-K
transactivation could serve as a new interventional strategy against these diseases in
immunocompromised patients. To address this hypothesis, we propose the following Specific Aims: 1) To
determine the clinical relevance and implications of HERV-K transactivation in development of KSHV-related
malignancies. 2) To identify the mechanisms through which KSHV-encoded major latent protein, LANA,
transactivates HERV-K in host cells. 3) To develop and assess the efficacy of targeting HERV-K
transactivation therapies against KSHV-related malignancies in vivo. Through these efforts, we aim to
illuminate putative mechanisms facilitating KSHV-related malignancies development by transactivation of
HERV-K as well as their clinical relevance and implication in patients. Additionally, these studies will provide
the framework for the development of interventional strategies targeting HERV-K transactivation and related
signaling molecules for the treatment of KSHV-related malignancies in high-risk immunocompromised patients.document fetched 2026-09-06 02:47