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Viral Determinants of Chronic Hepacivirus Infection

Award Number: R01AI185926
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: 06/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Viral Determinants of Chronic Hepacivirus Infection - Abstract The ability of the hepatitis C virus (HCV) to establish life-long chronic infection in most infected individuals makes it unique among RNA viruses. The molecular properties of the HCV genome and proteins are extensively characterized, but how they contribute to HCV persistence and immunopathogenesis remains poorly understood. This project seeks to identify the regions of the HCV genome that evolved to evade or modulate immunity to establish chronic infection. We isolated a rodent HCV-like virus (RHV) from a brown rat (Rattus norvegicus), RHV-rn1 (Rn-1), to develop surrogate animal models for HCV since Rn-1 established life-long chronic infection in rats and showed the potential for adaptation in lab mice. However, so far, Rn-1 studies have revealed two significant limitations. First, immunocompetent mice do not develop HCV-like prolonged or chronic infections. Second, although lab rats develop chronic infections, the lack of immunological and genetic resources limits their usefulness. A recent study described chronic Rn-1 infection in the collaborative cross (CC)- 071 mice; however, this CC strain is more susceptible to many Flaviviruses, and its mutated IRF3 gene, suppressed IFN signaling and T cell immunity, and diverse MHC haplotype limits its usefulness. Thus, an informative animal model to study the mechanism underlying spontaneous chronic HCV-like infections remains elusive and is critical for advancing this field. Finally, we identified a mouse-adapted variant Rn-2m that can establish prolonged or chronic viremia in normal lab mice. Subsequently, we identified the parent rat isolate Rn- 2 and its infection cleared within 3-4 weeks in mice, like Rn-1 infection. We also determined that chronic Rn-2m infection in mice leads to suppression of liver infiltrating leukocytes and virus-specific CD8 T cells, indicating that the mechanisms underlying the persistence of Rn-2m resemble that of HCV. Thus, there is a solid rationale for using Rn-2m as a surrogate for HCV to achieve the following two specific aims: Specific Aim 1 is to identify the genomic regions and mutations that allow Rn-2m to establish chronic infection. Specific Aim 2 is to compare the nature of infection and biological properties of Rn-2 and Rn-2m. We expect to identify the mutations (Aim- 1) that determine the unique biological properties of Rn-2m (Aim-2). This knowledge will gain new insights into the mechanism of HCV immune evasion. Additionally, proposed studies are critical for the informative use of this new animal model that develops spontaneous long-term chronic infection of a hepatotropic RNA virus.


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 = $665,540 )
2026	2026	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	3	4/29/2026	NON-COMPETING CONTINUATION	$665,540
														Subtotal = $665,540

Issue Date FY: 2025 ( Subtotal = $665,540 )
2025	2025	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	2	5/16/2025	NON-COMPETING CONTINUATION	$665,540
														Subtotal = $665,540

Issue Date FY: 2024 ( Subtotal = $665,540 )
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	5/29/2024	NEW	$598,985
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	1	9/3/2024	NEW	$66,555
														Subtotal = $665,540

Grand Total All Awards = $1,996,620

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Viral Determinants of Chronic Hepacivirus Infection

Award Number: R01AI185926

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: 06/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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