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.