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Viral and Host Determinants of Parvovirus Replication

Award Number: R01AI150877
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/27/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Viral and Host Determinants of Parvovirus Replication - Human bocavirus 1 (HBoV1), an autonomous human parvovirus, causes acute respiratory tract infections in young children. HBoV1 is unique among all small DNA viruses in that it expresses a noncoding RNA of 140 nucleotides from the 3' noncoding region after the capsid protein-coding region. This bocavirus-encoded small RNA (BocaSR) is exclusively expressed in the nucleus and plays an important role both in expression of viral nonstructural proteins and in viral DNA replication. HBoV1 infects and replicates in terminally-differentiated human airway epithelium cultured at an air-liquid interface (HAE-ALI), mimicking natural infection of human airways. Importantly, HBoV1 genome replication in the nondividing airway epithelial cells utilizes error-free Y- family DNA repair DNA polymerase (Pol) η and Pol κ, and BocaSR specifically interacts with viral nonstructural proteins. On the other hand, HBoV1 is a helper virus for the replication of adeno-associated virus (AAV) in HAE-ALI, and BocaSR also plays a key role in facilitating AAV Rep gene expression and DNA replication. Our central hypothesis is that HBoV1 has evolved to express a noncoding RNA to facilitate expression of the viral nonstructural proteins and their function in licensing viral DNA replication, which mimics a DNA repair process driven by error-free Pol η and Pol κ. In this application, we aim to reveal the mechanisms underlying the BocaSR-regulated expression of viral nonstructural proteins and viral DNA replication in the nucleus, and to understand the viral manipulation of the error-free Pol η and Pol κ in DNA synthesis. The BocaSR is novel as it is the first one found among all small DNA viruses and differs from other known RNA polymerase III (Pol III) transcribed viral noncoding RNAs by its unique properties in regulating viral gene expression and playing a direct role in viral DNA replication in the nucleus. Studying BocaSR-regulating parvovirus replication will contribute to the understanding of the functions of other viral noncoding RNAs in virus replication. In addition, knowledge in how parvovirus employs the DNA repair machinery for viral genome replication in nondividing cells will help us understand how a small DNA virus overcomes the barrier to replicate its genome outside of the cell cycle. Dissecting the viral and host determinants of HBoV1 genome replication will help the development of therapeutic approaches to prevent acute respiratory tract infections caused by HBoV1. Finally, deep understanding AAV DNA replication will help find a better way to produce recombinant AAV (rAAV) vector and to increase the efficacy of rAAV gene delivery, in particular, to nondividing cells.


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: 2024 ( Subtotal = $472,054 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Allergy and Infectious Diseases Research	001	5	5/21/2024	NON-COMPETING CONTINUATION	$47,206
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Allergy and Infectious Diseases Research	000	5	12/7/2023	NON-COMPETING CONTINUATION	$424,848
														Subtotal = $472,054

Issue Date FY: 2023 ( Subtotal = $472,054 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Allergy and Infectious Diseases Research	000	4	12/7/2022	NON-COMPETING CONTINUATION	$472,054
														Subtotal = $472,054

Issue Date FY: 2022 ( Subtotal = $472,054 )
2022	2022	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Allergy and Infectious Diseases Research	000	3	12/6/2021	NON-COMPETING CONTINUATION	$472,054
														Subtotal = $472,054

Issue Date FY: 2021 ( Subtotal = $472,054 )
2021	2021	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Allergy and Infectious Diseases Research	000	2	12/3/2020	NON-COMPETING CONTINUATION	$472,054
														Subtotal = $472,054

Issue Date FY: 2020 ( Subtotal = $485,304 )
2020	2020	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	4330 SHAWNEE MISSION PKWY	SHAWNEE MISSION	KS	66205	JOHNSON	USA	Allergy and Infectious Diseases Research	000	1	1/27/2020	NEW	$485,304
														Subtotal = $485,304

Grand Total All Awards = $2,373,520

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Viral and Host Determinants of Parvovirus Replication

Award Number: R01AI150877

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/27/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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