Evolution and diversity of the human hepatitis d virus genome

Abstract

Human hepatitis delta virus (HDV) is the smallest RNA virus in genome. HDV genome is divided into a viroid-like sequence and a protein-coding sequence which could have originated from different resources and the HDV genome was eventually constituted through RNA recombination. The genome subsequently diversified through accumulation of mutations selected by interactions between the mutated RNA and proteins with host factors to successfully form the infectious virions. Therefore, we propose that the conservation of HDV nucleotide sequence is highly related with its functionality. Genome analysis of known HDV isolates shows that the C-terminal coding sequences of large delta antigen (LDAg) are the highest diversity than other regions of protein-coding sequences but they still retain biological functionality to interact with the heavy chain of clathrin can be selected and maintained. Since viruses interact with many host factors, including escaping the host immune response, how to design a program to predict RNA genome evolution is a great challenging work.

Figure 1

HDV genome and replication. (a) Structural features of the HDV genome. The viral genome is a single-stranded circular RNA molecule composing of the viroid-like and the HDAg-coding domains. The ribozyme sequence (Rz) in the viroid-like domain is shown as a blue box. “A/G” in the HDAg-coding sequence indicates the nucleotide edited by the host ADAR leading to the synthesis of LDAg. The beginning and the end of the circular genome are labeled as 1/1683. (b) Replication of the HDV genome by the double rolling-circle replication model. The genome and antigenome of HDV are represented by blue or red circles and labeled as “G” or “αG”, respectively. The open blue or red lines represent the primary transcription products composed of multimeric units of the viral genome or antigenome, respectively. The location of Rz is denoted by the green or blue boxes in the genome and antigenome, respectively. Arrowheads indicate the self-cleavage site of the ribozyme.

Figure 2

Profiling of nucleotide identities of 43 HDV isolates. The vertical-axis represents percentage nucleotide identity and the horizontal-axis displays the whole viral genome sequence as the relative length of 1800 nucleotides due to the alignment. The ribozyme (Rz) in the genome and antigenome is indicated by the green or blue box, respectively. The relative genomic position of the the HDAg-coding sequence is also shown (red arrow-bar).