The Hepatitis C Virus Alternate Reading Frame (ARF) and Its Family of Novel Products: The Alternate Reading Frame Protein/F-Protein, the Double-Frameshift Protein, and Others

The hepatitis C virus (HCV) has an alternate reading frame (ARF) that overlaps the core protein gene. The overlapping reading frame distinguishes HCV from all of its known viral relatives, with the possible exception of GB virus B (GBV-B). The ARF is expressed during natural HCV infections and stimulates specific immune responses. Like several essential genes in other viruses (e.g., the human immunodeficiency virus polymerase) the ARF lacks an in-frame AUG start codon, suggesting that its expression involves unusual translation-level events. In vitro studies indicate that ribosomal frameshifting may be one of several processes that can lead to translation of the ARF. Frameshifting yields chimeric proteins that have segments encoded in the core gene covalently attached to amino acids encoded in the ARF. A consistent nomenclature for the ARF's protein products has yet to be established. We propose that all proteins that contain amino acids encoded in the + 1 ARF be called alternate reading frame proteins (ARFPs) and that specific ARFPs, such as the ARFP/F-protein, the double-frameshift protein, and the short form of core + 1, be designated as follows: ARFP/F (ARFP/F-protein), ARFP/DF (double-frameshift), and ARFP/S (short form of core + 1). The roles of ARFPs in the HCV life cycle are not yet known. There is a significant possibility that ARFPs may be responsible for some of the effects attributed to the core protein, given that most studies seeking to define the function of the core protein have employed materials likely to contain a combination of the core protein and ARFPs. The observed effects of the core protein include the induction of liver cancer, transformation of cells, and alterations of immune responses. This article reviews the discovery of ARF, describes the RNA structural elements involved in core/ARF gene expression, discusses possible functions of ARFPs, and considers the potential usefulness of ARFPs in vaccines. The HCV ARF is the focus of a new and rapidly expanding area of research, and the results of many ongoing studies are currently available in abstract form only. The preliminary nature of investigations that have not yet been reviewed by peers is noted in the text.