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The transactivation of human endogenous retrovirus (HERV)-K by oncogenic virus in HIV+ patients and development of targeted therapies

Award Number: R01DE035802
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/28/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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The transactivation of human endogenous retrovirus (HERV)-K by oncogenic virus in HIV+ patients and development of targeted therapies - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $647,465 )
2026	2026	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Oral Diseases and Disorders Research	000	1	8/28/2026	NEW	$647,465
														Subtotal = $647,465

Grand Total All Awards = $647,465

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The transactivation of human endogenous retrovirus (HERV)-K by oncogenic virus in HIV+ patients and development of targeted therapies

Award Number: R01DE035802

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/28/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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