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KSHV Replication and Trained Immunity

Award Number: R01DE035429
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: 08/01/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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KSHV Replication and Trained Immunity - This application is in response to the Notice of Special Interest (NOT-DE-25-038): Basic and Translational Oral Health Research Related with HIV/AIDS. As stated in the NOSI, oral malignancies in people living with HIV (PLWH) are associated with enhanced local and systemic inflammatory states and closely linked to other viruses, such as Kaposi’s sarcoma-associated herpesvirus (KSHV). It has been known that a significant amount of KSHV virion is identified in saliva and KSHV-linked KS tumors in the oral cavity. Our application aims to understand the association between inflammatory tissue environment and KSHV replication. Our hypothesis is that cellular inflammatory signaling support the activation of a KSHV gene enhancer, which helps to maintain reactivatable latent chromatin. We will focus on viral IL-6 (vIL-6) functions to dissect the contribution of inflammatory signaling in KSHV replication and reprogramming of infected cells. Because the oral cavity is constantly stimulated with inflammatory signaling by oral bacteria, we hypothesize that such tissue environment allows KSHV to maintain epigenetically active latent chromatin. Trained immunity is a recently recognized feature of immune regulation, in which immune cells respond more quickly and robustly to subsequent exposure to similar triggers via transcription memories. Accumulating evidence suggested the broad benefit of trained immunity for normal host defense when cytokine expression is tightly controlled. However, studies also linked the transcriptional memory with chronic inflammatory disease when cellular responses continue to be overly reactive. In cells infected with the KSHV, an inflammatory viral cytokine is strongly expressed from viral gene independent of the tightly controlled host immune signaling networks. A critical question also pertains to why KSHV evolutionarily maintains multiple cytokine homologues that activate host inflammatory responses. KSHV infection is indeed associated with inflammatory diseases, including Kaposi's sarcoma and KSHV inflammatory cytokine syndrome (KICS). KSHV genome is also frequently maintained (detected) in inflammatory tissues such as the oral cavity and KS tumor. Here, we propose to study a hypothesis that KSHV utilizes a host cell trained immunity function by inducing cellular inflammatory signaling for its replication with vIL-6. We will study how KSHV vIL-6 re-programs viral and host gene expression by activating respective genomic enhancer domains to form transcription memories. We will also reveal whether the inflammatory tissue microenvironment is associated with maintaining active (re-activatable) latent chromatin. Completing this study should increase our understanding of the vIL-6 function in viral replication and association with KSHV pathogenesis.


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: 2025 ( Subtotal = $505,056 )
2025	2025	UNIVERSITY OF CALIFORNIA, DAVIS	1850 RESEARCH PARK DR STE 300	DAVIS	CA	95618	YOLO	USA	Oral Diseases and Disorders Research	000	1	7/23/2025	NEW	$505,056
														Subtotal = $505,056

Grand Total All Awards = $505,056

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KSHV Replication and Trained Immunity

Award Number: R01DE035429

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: 08/01/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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