Targeting host factors: a novel rationale for the management of hepatitis C virus

Abstract

Hepatitis C is recognized as a major threat to global public health. The current treatment of patients with chronic hepatitis C is the addition of ribavirin to interferon-based therapy which has limited efficacy, poor tolerability, and significant expense. New treatment options that are more potent and less toxic are much needed. Moreover, more effective treatment is an urgent priority for those who relapse or do not respond to current regimens. A major obstacle in combating hepatitis C virus (HCV) infection is that the fidelity of the viral replication machinery is notoriously low, thus enabling the virus to quickly develop mutations that resist compounds targeting viral enzymes. Therefore, an approach targeting the host cofactors, which are indispensable for the propagation of viruses, may be an ideal target for the development of antiviral agents because they have a lower rate of mutation than that of the viral genome, as long as they have no side effects to patients. Drugs targeting, for example, receptors of viral entry, host metabolism or nuclear receptors, which are factors required to complete the HCV life cycle, may be more effective in combating the viral infection. Targeting host cofactors of the HCV life cycle is an attractive concept because it imposes a higher genetic barrier for resistance than direct antiviral compounds. However the principle drawback of this strategy is the greater potential for cellular toxicity.

Figure 1

Possible sites targeting host factors as a novel antiviral treatment. (1) Inhibition of HCV entry by anti-receptor antibodies; (2) Interference with the host metabolic factor involved in HCV replication; (3) Modulation of nuclear receptors involved in HCV replication; (4) Inhibition of HCV release. LDL-R: Low density lipoprotein receptor; HDL: High density lipoprotein; VLDL: Very low density lipoprotein; SRB-1: Scavenger receptor B1; FXR: Farnesoid X receptor; ER: Estrogen receptors; MTP: Microsomal triglyceride protein; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A.

Figure 2

Interaction between insulin and interferon-alfa signaling pathway. SOCs: Suppressor of cytokine signaling; PA2A: Protein phosphatase 2A; PI3K: Phosphatidil-Inositol 3-kinase; JAK: Janus kinase; STAT: Signal transduction and activator of transcription; TYK2: Tyrosine kinase 2; Dotted lines: Represent inhibition; Continuous lines: Represent activation.

Figure 3

Antiviral mechanism of Nitazoxanide. Dotted lines: Represent inhibition; Continuous lines: Represent activation.