Inhibition of intracellular hepatitis C virus replication by nelfinavir and synergistic effect with interferon‐α

Abstract

Liver diseases associated with hepatitis C virus (HCV) infection have become the major cause of mortality in patients with human immunodeficiency virus (HIV) infection since the introduction of highly active anti-retroviral therapy. HCV-related liver disease is more severe in HIV-infected patients than in non-HIV-infected patients, but the standard therapies used to treat chronic hepatitis C in HCV/HIV coinfected patients are the same as those for patients infected with HCV alone. HIV protease inhibitors might have potential to down-regulate HCV load of HCV/HIV coinfected patients. In this study, we evaluated the effects of nelfinavir on intracellular HCV replication using the HCV replicon system. We constructed an HCV replicon expressing a neomycin-selectable chimeric firefly luciferase reporter protein. Cytotoxicity and apoptosis induced by nelfinavir were assessed and synergism between nelfinavir and interferon (IFN) was calculated using CalcuSyn analysis. Nelfinavir dose-dependently repressed HCV replication at low concentrations (IC(50), 9.88 micromol/L). Nelfinavir failed to induce cytotoxicity or apoptosis at concentrations that inhibited HCV replication. Clinical concentrations of nelfinavir (5 micromol/L) combined with IFN showed synergistic inhibition of HCV replication in our replicon model. Our results suggest that the direct effects of nelfinavir on the HCV subgenome and its synergism with IFN could improve clinical responses to IFN therapy in HCV/HIV coinfected patients.

Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection

“…Most of the analyzed compounds (336) were inactive (Table S2. 4). As expected, some of the active antiviral compounds were already known to have antiviral activity against HCV [e.g., nelfinavir (21), nitazoxanide (22), and MK886 (23)]; others are known to be active against other viruses {e.g., haloperidol [EBV (24)] and amiodarone [SARS (25)]}. However, the ability of most of the compounds to inhibit HCV infection was unexpected.…”

“…Using an unbiased, miniaturized cell-based screening system, we discovered the anti-HCV properties of 33 clinically approved compounds. Although some of these compounds [e.g., nelfinavir (21), nitazoxanide (22), and MK886 (23)] were known to have antiviral activity, most were unexpected because their clinical indications are unrelated to treatment of viral infection. All of the antiviral compounds displayed activity at nontoxic concentrations and therefore may have therapeutic potential, especially because nitazoxanide, the compound displaying the lowest therapeutic index, is currently under clinical evaluation and has been reported to improve the outcome of standard IFN treatment (22).…”

Potential antiviral options against SARS-CoV-2 infection

“…Nelfinavir could also inhibit cell fusion caused by the SARS-CoV-2 S glycoprotein (https://doi.org/10.1101/2020.04.06.026476) (Musarrat et al, 2020). It also inhibits CHIKV, DENV, HCV, HSV-1, and SARS infections (https://doi.org/10.1039/C5RA14469H) (Kalu et al, 2014;Toma et al, 2009;Yamamoto et al, 2004). These studies warrant further investigations of the potential of nelfinavir alone or in combination with other drugs to inhibit SARS-CoV-2 infections.…”

HIV/HCV Co-infection: Pathogenesis, Clinical Complications, Treatment, and New Therapeutic Technologies

“…HAART can significantly decrease liver HCV necroinflammatory activity in co-infected patients with relatively preserved immune status, possibly by inhibiting HIV replication in the liver or decreasing level of proinflammatory cytokines [71]. In vitro, the HIV protease inhibitor nelfinavir inhibits HCV replication at concentrations showing no cytotoxicity and acts synergistically with IFN against HCV, suggesting that nelfinavir could improve the antiviral effects of IFN in co-infected patients [88]. …”

“…In vitro, the HIV protease inhibitor nelfinavir inhibits HCV replication at concentrations showing no cytotoxicity and acts synergistically with IFN against HCV, suggesting that nelfinavir could improve the antiviral effects of IFN in co-infected patients [88]. …”