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

Philippe A Gallay1, Michael D Bobardt1, Udayan Chatterji1

  • 1Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.

Plos One
|August 12, 2015
PubMed

Insights

A new in vitro model allows testing drugs against co-infection by Hepatitis C virus (HCV) and Human Immunodeficiency Virus type 1 (HIV-1). CPI-431-32, a cyclophilin inhibitor, effectively inhibits both viruses, even drug-resistant strains.

Area of Science:

  • Virology
  • Immunology
  • Pharmacology

Background:

  • Hepatitis C virus (HCV)-related liver disease is a major cause of illness and death in patients co-infected with HIV-1.
  • Existing direct-acting antivirals (DAAs) are often ineffective against HCV/HIV-1 co-infection, leading to higher rates of liver fibrosis, cirrhosis, and cancer.
  • A lack of suitable in vitro models has hindered the development of treatments for HCV/HIV-1 co-infection.

Purpose of the Study:

  • To develop a novel in vitro co-infection model for simultaneously studying HCV and HIV-1 replication.
  • To evaluate the efficacy of cyclophilin inhibitors (CypI), specifically CPI-431-32, against concurrent HCV and HIV-1 replication.
  • To compare the antiviral activity of CPI-431-32 with existing treatments like nelfinavir, daclatasvir, and alisporivir (ALV).

Main Methods:

  • Development of a co-culture system where HCV and HIV-1 replicate concurrently in human hepatocytes and CD4+ T-lymphocytes, respectively.
  • Treatment of the co-culture model with CPI-431-32, nelfinavir, and daclatasvir at pre- and post-infection stages.
  • Assessment of viral replication inhibition, including against drug-resistant variants, and evaluation of cyclophilin A (CypA) interactions.

Main Results:

  • CPI-431-32 demonstrated simultaneous inhibition of both HCV and HIV-1 replication in the co-infection model.
  • CPI-431-32 effectively inhibited drug-resistant HCV and HIV-1 variants, outperforming single-target antivirals.
  • CPI-431-32 showed superior efficacy over ALV in interrupting established co-infection, linked to potent inhibition of CypA isomerase activity and viral protein interactions.

Conclusions:

  • CPI-431-32 is a potent inhibitor of both HCV and HIV-1 replication, offering a promising therapeutic strategy for co-infected patients.
  • The novel co-infection model provides a valuable platform for evaluating antiviral agents targeting co-infections.
  • CPI-431-32 holds potential as a single agent or in combination with DAAs to combat HCV and HIV-1 infections.

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