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In contrast to DAAs, host-targeting agents (HTAs) interfere with host cellular factors that are essential in the viral replication cycle; as host genes, they are less likely to rapidly mutate under drug pressure, thus potentially exhibiting a high barrier to resistance, in addition to distinct mechanisms of action. We compared the effects of cyclosporin A (CsA), a HTA that targets cyclophilin A (CypA), to DAAs, including inhibitors of nonstructural protein 5A (NS5A), NS3\/4A, and NS5B, in Huh7.5.1 cells. Our data show that CsA suppressed HCV infection as rapidly as the fastest-acting DAAs. CsA and inhibitors of NS5A and NS3\/4A, but not of NS5B, suppressed the production and release of infectious HCV particles. Intriguingly, while CsA rapidly suppressed infectious extracellular virus levels, it had no significant effect on the intracellular infectious virus, suggesting that, unlike the DAAs tested here, it may block a post-assembly step in the viral replication cycle. Hence, our findings shed light on the biological processes involved in HCV replication and the role of CypA.<\/jats:p>","DOI":"10.3390\/v15040981","type":"journal-article","created":{"date-parts":[[2023,4,17]],"date-time":"2023-04-17T04:45:32Z","timestamp":1681706732000},"page":"981","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mechanisms of Action of the Host-Targeting Agent Cyclosporin A and Direct-Acting Antiviral Agents against Hepatitis C Virus"],"prefix":"10.3390","volume":"15","author":[{"given":"Dandan","family":"Liu","sequence":"first","affiliation":[{"name":"CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tanya P.","family":"Ndongwe","sequence":"additional","affiliation":[{"name":"CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Ji","sequence":"additional","affiliation":[{"name":"CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3790-8368","authenticated-orcid":false,"given":"Andrew D.","family":"Huber","sequence":"additional","affiliation":[{"name":"CS Bond Life Sciences Center, Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleftherios","family":"Michailidis","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA"},{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles M.","family":"Rice","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3202-2116","authenticated-orcid":false,"given":"Robert","family":"Ralston","sequence":"additional","affiliation":[{"name":"CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip R.","family":"Tedbury","sequence":"additional","affiliation":[{"name":"CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA"},{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan G.","family":"Sarafianos","sequence":"additional","affiliation":[{"name":"CS Bond Life Sciences Center, Department of Molecular Microbiology & Immunology, University of Missouri, Columbia, MO 65201, USA"},{"name":"Laboratory of Biochemical Pharmacology, Center for ViroScience and Cure, Department of Pediatrics, Emory University School of Medicine and Children\u2019s Healthcare of Atlanta, Atlanta, GA 30322, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,17]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022, June 16). 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