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Epigenetic Regulation of KSHV Genome Replication

Award Number: R01CA244074
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Epigenetic Regulation of KSHV Genome Replication - Kaposi's sarcoma Associated Herpesvirus (KSHV) or Human Herpesvirus 8 (HHV-8) is an oncogenic gammaherpesvirus known to be the causative agent of Kaposi's sarcoma (KS), and contributes to body cavity based lymphomas (BCBLs) or pleural effusion lymphomas (PELs) in AIDS patients. It is also associated with Multicentric Castleman's Disease (MCD). KSHV infects endothelial and human B cells with expression of a limited repertoire of genes that are linked to latent infection including the major latency associated nuclear antigen (LANA). KSHV undergoes two major replication modes; a lytic mode and a latent replication mode and in some instances there is an underlying low level of lytic replication that is seen during latency. This may be critical for the pathogenesis associated with the virus. KSHV latent replication is dependent on expression of LANA and initiates at the terminal repeats (TRs). LANA binding sites have been mapped to the TR elements and these sites recruit replication proteins ORCs and MCMs. We have shown that additional sites on the KSHV genome can initiate replication at other regions shown to also recruit ORC and MCMs. A unique technology referred to as single molecule analysis of replicated DNA (SMARD) was used to identify other regions capable of incorporating fluorescent nucleoside analogs during cell proliferation. We have also shown that the replication initiation zone is independent of the presence of LANA demonstrating that the KSHV genome is capable of initiating replication during latency at multiple sites along the genome. In this proposed application we will focus our efforts on understanding genome replication of the KSHV virus after de novo infection by focusing on the major regions of the genome that are activated for replication on infection of primary cells. We will determine the epigenetic programming of the genome, and higher order conformations which dictates genome sites containing firing capabilities for successful replication of the genome. Infected cells will be harvested at different time points of infection and the replication zones monitored by SMARD. We will compare these zones after infection of primary B- and endothelial cells. We will also quantitate the semi-conservative replication using a Meselson Stahl modified approach with real-time PCR. ChIP/ChIP-Seq and ChIA-PET-sequencing will be used to identify the genome regions associated with replication proteins ORCs, MCMs, chromatin modifying factors, and viral antigens. The analysis will determine the time points after the viral genome enters the nucleus to obtain a temporal picture of the transitional epigenetic marks that are determinants for replication. Furthermore, we will monitor the long range interactions, and conformation changes that occur on the viral genome during de novo infection to understand the contribution of epigenetics, higher order interactions and the viral and cellular antigens required for replication of the KSHV genome after de novo infection and establishment of latency. This will identify potential targets and development of intervention strategies for treatment of KSHV associated diseases.


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 = -$9,444 )
2026	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Control	000	5	12/9/2025	NON-COMPETING CONTINUATION	-$9,444
														Subtotal = -$9,444

Issue Date FY: 2023 ( Subtotal = $501,823 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Control	000	5	7/26/2023	NON-COMPETING CONTINUATION	$501,823
														Subtotal = $501,823

Issue Date FY: 2022 ( Subtotal = $501,823 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Control	000	4	7/21/2022	NON-COMPETING CONTINUATION	$501,823
														Subtotal = $501,823

Issue Date FY: 2021 ( Subtotal = $501,823 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Control	000	3	7/27/2021	NON-COMPETING CONTINUATION	$501,823
														Subtotal = $501,823

Issue Date FY: 2020 ( Subtotal = $495,670 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Control	000	2	7/2/2020	NON-COMPETING CONTINUATION	$495,670
														Subtotal = $495,670

Issue Date FY: 2019 ( Subtotal = $498,100 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Control	000	1	7/16/2019	NEW	$498,100
														Subtotal = $498,100

Grand Total All Awards = $2,489,795

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Epigenetic Regulation of KSHV Genome Replication

Award Number: R01CA244074

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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