Date of Award
Winter 12-2-2025
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Pharmacology and Experimental Therapeutics
First Advisor
Susan Uprichard
Abstract
Hepatitis C virus (HCV) continues to pose a threat to public health with currently 71 million people worldwide infected and at increased risk of developing liver steatosis, insulin resistance, chronic inflammation, fibrosis, cirrhosis, and worst-case scenario hepatocellular carcinoma. Viral entry into permissive cells is a commonly recognized drug target, however after replication and assembly of viral particles, many viruses spread to infect additional cells by two routes: cell-free (CF) and cell-to-cell (CTC) spread. While CTC spread shields the virus from neutralizing antibodies and is thought to contribute to the establishment and maintenance of chronic infection, traditional virus “entry inhibitors” are not designed to block this second means of spread. Therefore, using HCV as a model system, we determined the impact of inhibiting “viral spread” over the conventional strategy of inhibiting “viral entry” to establish the importance of CTC spread as a drug target. After characterizing a panel of compounds that inhibit CF entry or inhibit both CF and CTC spread, we tested the ability of these 2 groups of spread inhibitors to (1) synergize with HCV replication inhibitors, (2) block acute HCV spread and (3) prevent viral escape from replication inhibitors during combination treatment. Importantly, all 5 of the CF/CTC dual spread inhibitors synergized with HCV replication inhibitors, significantly slowed/prevented acute HCV spread, and slowed/prevented emergence of viral escape from replication inhibitors during co-treatment, while the CF entry inhibitors did not. As such, this work demonstrates the superior potential of “viral spread” as an antiviral drug target over the currently recognized target of “viral entry” and emphasizes the need to further characterize the mechanisms of viral CTC spread for future drug development.
Recommended Citation
Flores, Manuel German, "Viral Cell-to-Cell Spread: A Promising Antiviral Target" (2025). Dissertations. 4292.
https://ecommons.luc.edu/luc_diss/4292
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
