ABSTRACT
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.
KEYWORDS
Hepatitis C - alternate reading frame - ARFP - F-protein - frameshift - core
REFERENCES
Escherichia coli
.
EMBO J.
1988;
7
1503-1507
andrea.branch@mssm.edu
