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A splicing-generated protein of hepatitis B virus in chronic viral infection

Award Number: R56AI173101
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: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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A splicing-generated protein of hepatitis B virus in chronic viral infection - Abstract Chronic infection with hepatitis B virus (HBV) is a leading cause of liver cancer. The large (L) envelope protein interacts with core particles to initiate virion formation, and inhibits small (S) envelope protein secretion as subviral particles. In addition, L protein on virion surface binds to high-affinity HBV receptor to mediate viral entry. The polymerase (P) gene has its 5' end overlapping with 3' core gene, leading to much less P than core protein translation from the 3.5-kb pgRNA. The slightly longer pcRNA generates hepatitis B e antigen (HBeAg). Splicing of the 3.5-kb RNAs to remove a 0.5-kb intron causes frameshift to convert core protein into core-P fusion protein, and P protein into P-L fusion protein (p43). Low level of p43 was detected from in vitro transfection with cloned HBV genome, but it has not been further studied. We accidentally detected high level of extracellular p43 from artificial mutants with lost L protein expression, with further increase to the level of L protein from wild-type virus when combined with a nonsense mutation in core gene. This R01 grant application will investigate the regulation of p43 translation, stability, and examine its clinical significance and functional properties. We hypothesize that preferential translation of core-P fusion protein from spliced 3.5-kb RNA down regulates p43 at both translation initiation and protein stability, and that p43 can promote HBV virion secretion but reduce viral infectivity. Aim 1 will verify whether p43 is preferentially translated from spliced pgRNA or pcRNA, and clarify whether the nonsense mutation in core gene increases p43 through translational termination-reinitiation and/or lost expression of a p43 destabilizer. We will also examine whether p43 secretion is independent of S protein co-expression. In Aim 2 we will examine whether p43 protein level can be increased by core promoter mutations to augment pgRNA transcription, G1896A precore nonsense mutation to abolish HBeAg expression, and Q182* nonsense mutation in core gene to convert both core protein and core-P fusion protein into a slightly shortened core protein. p43 will also be monitored from viremic serum samples harboring such mutations. Aim 3 will determine the distribution of p43 on virions vs. subviral particles. A role of p43 in modulating HBV virion secretion and viral infectivity will be verified by blocking its expression through mutated splicing sites, followed by adding back increasing doses of p43 through co-transfection experiments. So far all the seven known HBV proteins are translated from unspliced RNAs. The proposed studies are significant in characterizing the only viral protein generated by RNA splicing, and in establishing its clinical relevance and functional properties. If p43 can inhibit HBV infectivity in a dose-dependent manner, that may open up a new antiviral approach against chronic HBV infection.


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 = -$48,095 )
2026	2024	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Allergy and Infectious Diseases Research	001	1	5/12/2026	NEW	$2,936
2026	2024	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Allergy and Infectious Diseases Research	000	1	5/5/2026	NEW	-$51,032
														Subtotal = -$48,095

Issue Date FY: 2024 ( Subtotal = $492,000 )
2024	2024	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Allergy and Infectious Diseases Research	000	1	6/25/2024	NEW	$442,802
2024	2024	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Allergy and Infectious Diseases Research	001	1	9/12/2024	NEW	$49,198
														Subtotal = $492,000

Grand Total All Awards = $443,905

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A splicing-generated protein of hepatitis B virus in chronic viral infection

Award Number: R56AI173101

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: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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