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Hepatitis C Virus Trafficking in Hepatocytes

Award Number: R01AI137514
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: 04/23/2026
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Hepatitis C Virus Trafficking in Hepatocytes - RESEARCH ABSTRACT: HEPATITIS C VIRUS TRAFFICKING IN HEPATOCYTES Many viruses have evolved distinct pathways of transmitting their infection between cells. This viral spread involves canonical pathways that release unprotected virions from the infected cell (thus potentially exposing the virion to neutralizing antibodies) and/or pathways that shield the virion from the humoral response (cell-cell spread, syncytia formation, and the release of virions in extra-cellular vesicles). Viral egress pathways that evade the humoral response are especially important to understand given the potential importance of manipulating viral susceptibility to this critical arm of adaptive immunity. Most viruses of the Flaviviridae appear to use both mechanisms of viral egress. We and others previously characterized the pathway of canonical hepatitis C virus (HCV) release, while canonical dengue virus (DENV) secretion has also been well characterized. In contrast, noncanonical pathways of virion spread in the Flaviridae are poorly understood. Our lab has a longstanding interest in Flaviviridae entry and spread. In our prior funding period, we developed a multi-pronged analysis (host genetics, pharmacological inhibition and single particle imaging) of polarized hepatoma organoids to characterize HCV entry and egress. The work established the most complete, detailed pathway of HCV entry, in addition to extensive preliminary data on HCV cell-cell spread. We expanded these studies into the non-canonical spread of DENV, focusing on a process we discovered years ago: DENV-induced lipophagy, which is the selective autophagic mobilization of lipid droplet stores to stimulate lipid metabolism. This process has been associated with the non-canonical release of DENV into extra-cellular vesicles. We have identified a central cellular player in this process: the selective autophagy adaptor NBR1. In this R01 renewal application, we will focus on extending and expanding our studies on HCV and DENV non-canonical virion spread. In the case of HCV, we developed quantitative cell-cell spread assays and identified putative cellular secretion pathways and cargo adaptors that modulate cell-cell spread. We propose to characterize the significance of these pathways using imaging of our 3-dimensional polarized hepatoma spheroid system. Additionally, we will collaborate for an ultra-structural analysis of HCV-infected hepatocyte cell-cell junctions cryoelectron microscopy tomography (cryo-ET). For DENV non-canonical spread, we will validate a rove for NBR1 and lipophagy in the cell-cell spread of DENV. We will then characterize the pathway of non-canonical release of DENV virions. Finally, we will perform ultrastructural analysis of the NBR1-dependent DENV containing extra-cellular vesicles using cryo-ET. The specific aims are: Aim 1. Characterize the pathway(s) of HCV cell-cell spread in infected hepatocytes. Aim 2. Characterize the NBR1-dependent pathway of non-canonical DENV egress.


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 = $479,779 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	6	4/27/2026	COMPETING CONTINUATION	$479,779
														Subtotal = $479,779

Issue Date FY: 2025 ( Subtotal = -$2,841 )
2025	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	5	7/9/2025	NON-COMPETING CONTINUATION	-$2,841
														Subtotal = -$2,841

Issue Date FY: 2023 ( Subtotal = $444,492 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	5	4/5/2023	SUPPLEMENT FOR EXPANSION	$45,444
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	5	2/14/2023	NON-COMPETING CONTINUATION	$399,048
														Subtotal = $444,492

Issue Date FY: 2022 ( Subtotal = $483,374 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	4	2/22/2022	SUPPLEMENT FOR EXPANSION	$84,326
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	4	2/16/2022	NON-COMPETING CONTINUATION	$399,048
														Subtotal = $483,374

Issue Date FY: 2021 ( Subtotal = $444,492 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	3	8/23/2021	SUPPLEMENT FOR EXPANSION	$45,444
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	3	2/18/2021	NON-COMPETING CONTINUATION	$399,048
														Subtotal = $444,492

Issue Date FY: 2020 ( Subtotal = $399,048 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	2	2/20/2020	NON-COMPETING CONTINUATION	$399,048
														Subtotal = $399,048

Issue Date FY: 2019 ( Subtotal = $399,048 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	1	3/4/2019	NEW	$399,048
														Subtotal = $399,048

Grand Total All Awards = $2,647,392

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Hepatitis C Virus Trafficking in Hepatocytes

Award Number: R01AI137514

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: 04/23/2026

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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