As a deficient virus due to the lack of envelope
proteins, hepatitis D virus (HDV) causes chronic or fulminant "
delta hepatitis" only in people with simultaneous hepatitis B virus (HBV)
infection. HBV encodes three types of
surface proteins known as small (S), medium (M) and large (L) envelope
proteins. All three types of HBV
surface antigens (HBsAgs) are present on HDV virions. The envelopment process of HDV occurs through interactions between the HDV
ribonucleoprotein (RNP) complex and HBV HBsAgs. While
HBsAg is the only
protein required by HDV, the exact interaction sites between the S
protein and pre-mature HDV are not well defined yet. In fact, these sites are distributed along the S
protein with some hot spots for the envelopment process. Moreover, in most clinically studied samples, HDV
infection is associated with a dramatically reduced HBV viral load, temporarily or permanently, while
HBsAg resources are available for HDV packaging. Thus, beyond interacting with HBV envelope
proteins, controlling mechanisms exist by which HDV inhibits HBV-DNA replication while allowing a selective transcription of HBV
proteins. Here we discuss the molecular interaction sites between
HBsAg and the HDV-RNP complex and address the proposed indirect mechanisms, which are employed by HBV and HDV to facilitate or inhibit each other's viral replication. Understanding molecular interactions between HBV and HDV may help to design novel therapeutic strategies for
delta hepatitis.