The Novel Cyclophilin Inhibitor CPI-431-32 Concurrently Blocks HCV and HIV-1 Infections via a Similar Mechanism of Action.
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.
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
Philippe A
PA
Gallay
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
Michael D
MD
Bobardt
Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
Udayan
U
Chatterji
Ciclofilin Pharmaceuticals Inc., San Diego, California, United States of America.
Daniel J
DJ
Trepanier
Ciclofilin Pharmaceuticals Inc., San Diego, California, United States of America.
Daren
D
Ure
Ciclofilin Pharmaceuticals Inc., San Diego, California, United States of America.
Cosme
C
Ordonez
Ciclofilin Pharmaceuticals Inc., San Diego, California, United States of America.
Robert
R
Foster
D000998:Antiviral Agents / Q000494:pharmacology*; D036022:Capsid Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D060085:Coinfection; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D024882:Drug Resistance, Viral / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D048348:Reverse Transcription / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D036022:Capsid Proteins; D003524:Cyclosporins; D021983:Cyclophilins