Overlapping structure of hepatitis B virus (HBV) genome and immune selection pressure are critical forces modulating HBV evolution

Abstract

How the overlap between the hepatitis B virus (HBV) reverse transcriptase (RT) and HBV S antigen (HBsAg) genes modulates the extent of HBV genetic variability is still an open question, and was investigated here. The rate of nucleotide conservation (¡1 % variability) followed an atypical pattern in the RT gene, due to an overlap between RT and HBsAg (69.9 % nucleotide conservation in the overlapping region vs 41.2 % in the non-overlapping region; P,0.001), with a consequently lower rate of synonymous substitution within the overlapping region [median(interquartile range)dS53.1(1.5-7.4) vs 20.1(10.6-30.0); P53.249¾10"22 ]. The most conserved RT regions were located within the YMDD motif and the N-terminal parts of the palm and finger domains, critical for RT functionality. These regions also corresponded to highly conserved HBsAg domains that are critical for HBsAg secretion. Conversely, the genomic region encoding the HBsAg antigenic loop (where immune-escape mutations are localized) showed a sharp decrease in the extent of conservation (40.6 %), which was less pronounced in the setting of human immunodeficiency virus (HIV)-driven immune suppression (48.8 % in HIV-HBV coinfection vs 21.5 % in mono-infected patients; P50.020). In conclusion, the overlapping reading frame and the immune system appear to have shaped the patterns of RT and HBsAg genetic variability. Highly conserved regions in RT and HBsAg may deserve further attention as novel therapeutic targets.About 2 billion people worldwide are infected with hepatitis B virus (HBV), and about 350 million presently live with chronic HBV infection (WHO, 2012), thus making this viral infection a global health concern.3On behalf of the ICoNA study group.

A strong conservative tendency in HBV transcriptase (RT): a majority of natural RT mutations derived from the S gene

“…P gene is functionally divided into four domains, one of which encodes reverse transcriptase (RT) composed by 344 amino acids (aa). It consists of seven functional domains (G, F, A, B, C, D and E) and five interdomains connecting these domains (F-A, A-B, B-C, C-D and D-E), which is the target of nucleos(t)ide analogues (NAs) (3,4).…”

Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1

“…This variation can be the result of antigenic drift, such as in the case of the influenza virus (30,31), or the result of pathogen evolution in response to immuneselective pressure, such as in the case of HIV (32)(33)(34) and both hepatitis B (35) and C (36). Antigenic variation can be addressed through the use of polyvalent vaccines, and understanding the mechanisms that guide the polyvalent immune response is critical to vaccine design.…”

Genetic variability of hepatitis B virus in Uruguay: D/F, A/F genotype recombinants

“…This means that the third position of the polymerase codons correspond to the second position of the S codons. Nucleotide substitutions at the polymerase second codon position affects the amino acid in both RT and HBsAg, and this position has the highest degree of conservation in its nucleotide and amino acid sequence, like the RNAseH region of the polymerase or the PreS1 region [68,69]. This could explain why we did not find recombination events within this conserved region.…”

“…An F3/A1 recombinant was found in an Afro-Colombian population [68], and an F4/D2 recombinant was reported in Argentina [69]. ''Hot spots'' for HBV genome recombination events have been described within the core region, pre-S1, pre-S2/S, polymerase, and X gene [69]. The recombination points identified for the three Uruguayan strains were located within the HBV genome ''hot spots'' described previously.…”

“…HBV recombinants in Latin America have been reported previously [31,67]. An F3/A1 recombinant was found in an Afro-Colombian population [68], and an F4/D2 recombinant was reported in Argentina [69]. ''Hot spots'' for HBV genome recombination events have been described within the core region, pre-S1, pre-S2/S, polymerase, and X gene [69].…”