Potential treatment options and future research to increase hepatitis C virus treatment response rate

Abstract

Hepatitis C virus (HCV) is a liver-tropic blood-borne pathogen that affects more than 170 million people worldwide. Although acute infections are usually asymptomatic, up to 90% of HCV infections persist with the possibility of long-term consequences such as liver fibrosis, cirrhosis, steatosis, insulin resistance, or hepatocellular carcinoma. As such, HCV-associated liver disease is a major public health concern. Although the currently available standard of care therapy of pegylated interferon α plus ribavirin successfully treats infection in a subset of patients, the development of more effective, less toxic HCV antivirals is a health care imperative. This review not only discusses the limitations of the current HCV standard of care but also evaluates upcoming HCV treatment options and how current research elucidating the viral life cycle is facilitating the development of HCV-specific therapeutics that promise to greatly improve treatment response rates both before and after liver transplantation.

Figure 1

The HCV genome and gene products – potential STAT-C targets. The 9.6-kb HCV RNA genome encoding a single open-reading frame (ORF) flanked by highly structured 5′ and 3′ untranslated regions (UTRs) is depicted. The internal ribosome entry site (IRES) located in the 5′ UTR-mediated translation of a polyprotein precursor that is cotranslationally cleaved (arrows) by host (SPP = maroon and SP = blue) and viral (NS2/3 = black and NS3/4a = orange) proteases into mature structural (green boxes) and nonstructural (purple boxes) viral proteins. Descriptive titles and known activities are listed for each viral protein.

Figure 2

The HCV lifecycle and potential antiviral drug targets. (1) Binding of the virus to cell surface receptors; (2) HCV entry into the cell via endocytosis; (3) release of the viral genome into cytoplasm (ie, fusion and uncoating); (4) IRES-mediated polyprotein translation; (5) polyprotein processing; (6) formation of viral replication complexes (ie, the membranous web); (7) viral RNA replication; (8) packaging and assembly of progeny virions; (9) virion maturation and release via the cellular secretory system. Although depicted separately, many of these viral functions likely occur concurrently and within close proximity. in particular, we show here lipid droplets (LDs), which are thought to be the site of HCV particle assembly, closely associated with the membranous web; however, the spatial relationship of these two viral activities remains to be determined.