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The Novel Cyclophilin Inhibitor CPI-431-32 Concurrently Blocks HCV and HIV-1 Infections via a Similar Mechanism of Action.

Abstract
HCV-related liver disease is the main cause of morbidity and mortality of HCV/HIV-1 co-infected patients. Despite the recent advent of anti-HCV direct acting antivirals (DAAs), the treatment of HCV/HIV-1 co-infected patients remains a challenge, as these patients are refractory to most therapies and develop liver fibrosis, cirrhosis and liver cancer more often than HCV mono-infected patients. Until the present study, there was no suitable in vitro assay to test the inhibitory activity of drugs on HCV/HIV-1 co-infection. Here we developed a novel in vitro "co-infection" model where HCV and HIV-1 concurrently replicate in their respective main host target cells--human hepatocytes and CD4+ T-lymphocytes. Using this co-culture model, we demonstrate that cyclophilin inhibitors (CypI), including a novel cyclosporin A (CsA) analog, CPI-431-32, simultaneously inhibits replication of both HCV and HIV-1 when added pre- and post-infection. In contrast, the HIV-1 protease inhibitor nelfinavir or the HCV NS5A inhibitor daclatasvir only blocks the replication of a single virus in the "co-infection" system. CPI-431-32 efficiently inhibits HCV and HIV-1 variants, which are normally resistant to DAAs. CPI-431-32 is slightly, but consistently more efficacious than the most advanced clinically tested CypI--alisporivir (ALV)--at interrupting an established HCV/HIV-1 co-infection. The superior antiviral efficacy of CPI-431-32 over ALV correlates with its higher potency inhibition of cyclophilin A (CypA) isomerase activity and at preventing HCV NS5A-CypA and HIV-1 capsid-CypA interactions known to be vital for replication of the respective viruses. Moreover, we obtained evidence that CPI-431-32 prevents the cloaking of both the HIV-1 and HCV genomes from cellular sensors. Based on these results, CPI-431-32 has the potential, as a single agent or in combination with DAAs, to inhibit both HCV and HIV-1 infections.
AuthorsPhilippe A Gallay, Michael D Bobardt, Udayan Chatterji, Daniel J Trepanier, Daren Ure, Cosme Ordonez, Robert Foster
JournalPloS one (PLoS One) Vol. 10 Issue 8 Pg. e0134707 ( 2015) ISSN: 1932-6203 [Electronic] United States
PMID26263487 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antiviral Agents
  • Capsid Proteins
  • Cyclosporins
  • Cyclophilins
Topics
  • Antiviral Agents (pharmacology)
  • Capsid Proteins (metabolism)
  • Cell Line
  • Cells, Cultured
  • Coculture Techniques
  • Coinfection
  • Cyclophilins (antagonists & inhibitors, metabolism)
  • Cyclosporins (pharmacology)
  • Drug Resistance, Viral (drug effects)
  • HIV Infections (drug therapy, virology)
  • HIV-1 (drug effects)
  • Hepacivirus (drug effects)
  • Hepatitis C (drug therapy, virology)
  • Humans
  • Protein Binding (drug effects)
  • Reverse Transcription (drug effects)
  • Virus Replication (drug effects)

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