# Restoration of immunity and function with DAA treatment in HCV infection

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $412,500

## Abstract

PROJECT SUMMARY
Chronic HCV infection afflicts 180 million individuals throughout the world. The majority of individuals infected
with HCV develop persistence, suggesting that HCV successfully subverts innate and adaptive immune
responses. Mathematical models have projected a massive increase in the number of patients developing
HCV-related complications (e.g., cirrhosis, hepatocellular carcinoma) in the next few decades as the population
ages. Although hepatocytes comprise the majority of the total cell population within the liver, the non-
parenchymal liver cells have been increasingly recognized as playing central roles in chronic inflammation and
complications from HCV infection. Although the development of direct-acting antivirals (DAAs) has led to
nearly miraculous cure rates [compared to interferon (IFN)-based therapy], a number of important questions
remain unanswered that demand further study. To what extent is immunity restored in patients cured with
DAAs and what are the effects on cross-talk between the multiple cell types within the hepatic
microenvironment? What effect does HCV cure have on inflammation, fibrosis development, and further
hepatic decompensation? The answers to these questions have remained elusive and have implications for
other liver disease. Here, we will define the breadth and pace of reconstitution of hepatic and peripheral innate
and adaptive immunity induced by DAA therapy in patients with chronic HCV infection. We will also determine
how DAA-mediated viral eradication affects epigenetic reprogramming of HCV-specific CTLs. A large cohort
of already-enrolling patients, including those who have previously failed DAA therapy and have evidence of
resistance-associated variants, will be serially studied according to pre-treatment viral level and fibrosis stage.
Next, we will characterize the complex communication between hepatocytes and nonparenchymal cells
(NPCs) in HCV infection and the impact of DAA-mediated viral elimination. We hypothesize that exosomes
play important roles in intercellular communication that is intricately linked to the cell origin of the exosomes, as
well as the biologic milieu; exosomes can shuttle HCV and biologically active molecules from infected
hepatoma cells to a variety of NPC. We will examine how purified exosomes derived from HCV-infected and
DAA-cured hepatocytes differentially trigger responses in Kupffer cells (KCs), liver sinusoidal endothelial cells
(LSECs) and HSCs. We will comprehensively characterize the exosomal content following HCV exposure and
determine which components, including microRNAs, either amplify or attenuate inflammatory or fibrotic
pathways. If successful, these studies would provide novel insights into the mechanisms mediating
viral clearance, residual inflammation, and liver injury (fibrosis) and have broad-reaching relevance in
the rapidly changing field of HCV, potentially opening up new avenues of research into this highly
prevalent liver disease worldwi...

## Key facts

- **NIH application ID:** 9859204
- **Project number:** 5R01AI120622-05
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** HUGO Ramon ROSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,500
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859204

## Citation

> US National Institutes of Health, RePORTER application 9859204, Restoration of immunity and function with DAA treatment in HCV infection (5R01AI120622-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9859204. Licensed CC0.

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