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Role of Lipid Droplets in Hepatitis C Virus Infection

Award Number: R01AI097552
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: 03/01/2014
PERIOD OF PERFORMANCE END DATE: 04/30/2021

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Role of Lipid Droplets in Hepatitis C Virus Infection - DESCRIPTION (provided by applicant): The hepatitis C virus (HCV) epidemic is a global health problem and affects ~170 million people worldwide. In ~80% of cases, viral infection becomes chronic, rendering HCV a leading cause of liver-related morbidity and mortality. A common symptom of chronic HCV infection is steatosis, the abnormal accumulation of lipid droplets in the liver. Steatosis is observed in ~55% of chronically HCV-infected patients and represents an important risk factor for the development of liver fibrosis and cancer. The viral nucleocapsid core expressed in livers of transgenic mice recapitulates this condition; core itself also localizes to the surface of lipid droplets (LDs), a process critical for the assembly of progeny virions at membranes in close proximity to LDs. We recently identified the triglyceride-synthesizing enzyme DGAT1 as a novel host factor for HCV assembly (Herker et al, Nat. Med. 2010). In cells lacking DGAT1 or treated with a DGAT1 inhibitor, core cannot localize to LDs and cannot recruit viral RNA to neighboring endoplasmic reticulum membranes for encapsidation. As a consequence, HCV particle production is severely impaired. We recently published three additional studies that demonstrate 1) that a second HCV protein, NS5A, interacts with DGAT1 and requires DGAT1 for LD localization (Camus et al, J. Biol. Chem. 2013), 2) that core at the surface of LDs decreases the lipolysis of these LDs, thereby causing steatosis (Harris, Herker et al, J. Biol. Chem. 2012), and 3) that LDs play a larger role in HCV infection with a new involvement in HCV RNA replication via a new interaction between the LD- associated protein TIP47 and NS5A (Vogt et al, PLoS Pathog. 2013). We seek to study in molecular detail the role of LDs as critical host organelles in the HCV lifecycle. We propose three experiments. 1) To define the role of DGAT1 in recruiting HCV proteins to LDs. We will test the hypothesis that a tripartite complex of DGAT1, NS5A and core has evolved to co-recruit core and NS5A to DGAT1-generated LDs. We will also determine if NS5A and core are new protein targets for the acyltransferase activity of DGAT1. 2) To determine how the HCV core protein inhibits lipolysis. We will test whether core at the surface of LDs interferes with the recruitment or activity of the triglyceride lipases ATGL/PNPLA2 and PNPLA3, thus inhibiting lipolysis. Because patients infected with different HCV genotypes are at different risks to develop steatosis, we will compare anti-lipolytic activities of core proteins from different viral genotypes. 3) To explore how the NS5A-TIP47 interaction regulates HCV RNA replication. We will determine if LDs serve a dual role in HCV infection: one as membrane and energy sources for HCV RNA replication and another as assembly platforms. We will determine whether binding of NS5A to TIP47 plays an important role in this process. Collectively, our proposed studies will bring new molecular insight into the role of LDs in the HCV lifecycle and may uncover potential novel therapeutic strategies to treat chronic HCV disease.


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: 2022 ( Subtotal = -$32,267 )
2022	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	11/17/2021	NON-COMPETING CONTINUATION	-$32,267
														Subtotal = -$32,267

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	12/11/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $477,500 )
2018	2018	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	4/5/2018	NON-COMPETING CONTINUATION	$477,500
														Subtotal = $477,500

Issue Date FY: 2017 ( Subtotal = $477,500 )
2017	2017	J.DAVID GLADSTONE INSTITUTES	1650 OWENS ST	SAN FRANCISCO	CA	94158	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	4	3/27/2017	NON-COMPETING CONTINUATION	$477,500
														Subtotal = $477,500

Issue Date FY: 2016 ( Subtotal = $477,500 )
2016	2016	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	3	4/21/2016	NON-COMPETING CONTINUATION	$477,500
														Subtotal = $477,500

Issue Date FY: 2015 ( Subtotal = $477,500 )
2015	2015	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	2	3/25/2015	NON-COMPETING CONTINUATION	$477,500
														Subtotal = $477,500

Issue Date FY: 2014 ( Subtotal = $477,500 )
2014	2014	J DAVID GLADSTONE INSTITUTES	POST OFFICE BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	1	7/18/2014	NEW	$0
2014	2014	J DAVID GLADSTONE INSTITUTES	P.O. BOX 419100	SAN FRANCISCO	CA	94141	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	2/20/2014	NEW	$477,500
														Subtotal = $477,500

Grand Total All Awards = $2,355,233

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Role of Lipid Droplets in Hepatitis C Virus Infection

Award Number: R01AI097552

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: 03/01/2014

PERIOD OF PERFORMANCE END DATE: 04/30/2021

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