Immune-Induced Evolutionary Selection Focused on a Single Reading Frame in Overlapping Hepatitis B Virus Proteins

Abstract

Viruses employ various means to evade immune detection. Reduction of CD8؉ T cell epitopes is one of the common strategies used for this purpose. Hepatitis B virus (HBV), a member of the Hepadnaviridae family, has four open reading frames, with about 50% overlap between the genes they encode. We computed the CD8 ؉ T cell epitope density within HBV proteins and the mutations within the epitopes. Our results suggest that HBV accumulates escape mutations that reduce the number of epitopes. These mutations are not equally distributed among genes and reading frames. While the highly expressed core and X proteins are selected to have low epitope density, polymerase, which is expressed at low levels, does not undergo the same selection. In overlapping regions, mutations in one protein-coding sequence also affect the other protein-coding sequence. We show that mutations lead to the removal of epitopes in X and surface proteins even at the expense of the addition of epitopes in polymerase. The total escape mutation rate for overlapping regions is lower than that for nonoverlapping regions. The lower epitope replacement rate for overlapping regions slows the evolutionary escape rate of these regions but leads to the accumulation of mutations more robust in the transfer between hosts, such as mutations preventing proteasomal cleavage into epitopes.

Mother-to-child transmission of hepatitis B virus: Evolution of hepatocellular carcinoma-related viral mutations in the post-immunization era

“…In the initial immunotolerant phase, viral load is high, hepatitis B e antigen (HBeAg) is positive. With the progression of chronic infection, HBV mutations gradually occur, especially during HBeAg seroconversion [6][7][8][9]. HBV accumulates mutations via minimizing the epitopes recognized by CD8 + T cells, particularly in the enhancer II/basal core promoter/precore (EnhII/BCP/preC) region and the preS/S regions.…”

HLA-DPPolymorphisms Affect the Outcomes of Chronic Hepatitis B Virus Infections, Possibly through Interacting with Viral Mutations

“…Only the HBV strains/variants best adapted to the host immune system will survive and thrive in liver. HBV accumulates mutations via minimizing the total number of epitopes recognized by CD8 ϩ T cells, particularly in the HBx and the pre-S1/pre-S2/S regions, to avoid immune clearance (25). These HBV mutations are probably selected via virus-immune interactions in the inflammatory microenvironment.…”

Estimate of Within Population Incremental Selection Through Branch Imbalance in Lineage Trees

“…The algorithms' quality was systematically validated versus epitope databases and was found to induce low false positive (FP) and false negative (FN) error rates. These algorithms were validated in multiple previous analyses (35)(36)(37)(38)(39)(40)(41)(42).…”