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Genetic Viral and Host Adaptations to Breach Species Barriers of HCV

Award Number: R01AI107301
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: 07/01/2013
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Genetic Viral and Host Adaptations to Breach Species Barriers of HCV - Project summary Hepatitis C virus (HCV) is an important and underreported infectious disease, causing chronic infection in ~58 million people worldwide. The CDC estimates there are ~67,000 new cases of HCV every year in the US and about 20,000 deaths annually, making HCV more deadly than 60 other infectious diseases combined, including HIV. However, the underlying mechanisms that lead to chronic HCV infection followed by end-stage liver disease are poorly understood. Although chronic hepatitis C can now be effectively treated with direct-acting antivirals, a vaccine to prevent transmission remains a high priority due to extreme treatment costs (up to $50,000 for a 12- week course) and the irreversibility of virally induced liver damage even in “cured” individuals. Efforts to better understand HCV and develop effective vaccines have been limited by the lack of small animal models for this virus, which only robustly infects humans and chimpanzees. In the proposed work, we will build on our substantial research findings to meet this need for an immunocompetent animal model that will allow us to not only systematically analyze the molecular basis of barriers to interspecies HCV transmission but also how such a model could be leveraged for assessing vaccine candidates. Towards this end, we recently identified a highly murine-adapted HCV variant, coined Mad18, with increased replicative capacity in primary murine hepatocytes, which historically only poorly support HCV replication. Through continued passaging of Mad18 in HCV entry factor transgenic (EFT) mice with impaired antiviral signaling (EFT Stat1-/-), we aim to further adapt this variant to a murine physiological environment and define the underpinning biological mechanism (Aim 1). Our considerable experience with studying viral infections in genetically humanized mice will be utilized to also study Mad18 and its derivatives in a variety of new mouse lines, including immunocompetent models, with targeted changes to increase their support of HCV infection (Aim 2). Our observations of persistent HCV infection in hepatocytes from immunocompetent HCV entry factor knock-in mice that also express human TRIM26 (EFT TRIM26[h/h]) put us in a strong position for these in vivo studies. The Ploss lab has made many seminal contributions to the field and will be aided in this important work by our long-standing collaborators Drs. Schwartz (Weill Cornell) and Pietschmann (Twincore, Germany). Our work will advance the field of HCV research by making progress in deciphering the mechanism underlying the exquisitely narrow host tropism and the development of small animal models suitable for studying HCV infection and immune responses, a necessary precursor to improving treatment and developing vaccines.


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 = $531,385 )
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	12	12/23/2024	NON-COMPETING CONTINUATION	$531,385
2025	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	002	11	2/12/2025	COMPETING CONTINUATION	$0
2025	2022	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	001	10	2/12/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $531,385

Issue Date FY: 2024 ( Subtotal = $577,427 )
2024	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	001	11	2/15/2024	COMPETING CONTINUATION	$520,943
2024	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	002	11	9/3/2024	COMPETING CONTINUATION	$56,484
2024	2022	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	10	2/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $577,427

Issue Date FY: 2022 ( Subtotal = $466,302 )
2022	2022	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	10	6/15/2022	NON-COMPETING CONTINUATION	$466,302
														Subtotal = $466,302

Issue Date FY: 2021 ( Subtotal = $474,798 )
2021	2021	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	9	6/14/2021	NON-COMPETING CONTINUATION	$474,798
														Subtotal = $474,798

Issue Date FY: 2020 ( Subtotal = $477,137 )
2020	2020	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	8	6/25/2020	NON-COMPETING CONTINUATION	$477,137
														Subtotal = $477,137

Issue Date FY: 2019 ( Subtotal = $473,320 )
2019	2019	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	004	7	6/28/2019	NON-COMPETING CONTINUATION	$473,320
2019	2018	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	6	10/30/2018	COMPETING CONTINUATION	$0
2019	2018	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	003	6	3/28/2019	COMPETING CONTINUATION	$0
2019	2018	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	002	6	11/30/2018	COMPETING CONTINUATION	$54,474
2019	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	5	11/30/2018	NON-COMPETING CONTINUATION	-$54,474
														Subtotal = $473,320

Issue Date FY: 2018 ( Subtotal = $506,524 )
2018	2018	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	6	6/15/2018	COMPETING CONTINUATION	$506,524
														Subtotal = $506,524

Issue Date FY: 2017 ( Subtotal = $402,500 )
2017	2017	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	001	5	6/14/2017	NON-COMPETING CONTINUATION	$402,500
2017	2015	ROCKEFELLER UNIVERSITY, THE	1230 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	12/27/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,500

Issue Date FY: 2016 ( Subtotal = $402,500 )
2016	2016	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	4	6/15/2016	EXTENSION WITH OR WITHOUT FUNDS	$402,500
														Subtotal = $402,500

Issue Date FY: 2015 ( Subtotal = $402,500 )
2015	2015	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	3	6/22/2015	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2014 ( Subtotal = $402,500 )
2014	2014	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	2	6/18/2014	NON-COMPETING CONTINUATION	$402,500
														Subtotal = $402,500

Issue Date FY: 2013 ( Subtotal = $378,350 )
2013	2013	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	000	1	6/24/2013	NEW	$378,350
2013	2013	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Allergy and Infectious Diseases Research	001	1	7/17/2013	NEW	$0
														Subtotal = $378,350

Grand Total All Awards = $5,495,243

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Genetic Viral and Host Adaptations to Breach Species Barriers of HCV

Award Number: R01AI107301

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: 07/01/2013

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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