Dataset Information

Rapid protein sequence evolution via compensatory frameshift is widespread in RNA virus genomes.

ABSTRACT:

Background

RNA viruses possess remarkable evolutionary versatility driven by the high mutability of their genomes. Frameshifting nucleotide insertions or deletions (indels), which cause the premature termination of proteins, are frequently observed in the coding sequences of various viral genomes. When a secondary indel occurs near the primary indel site, the open reading frame can be restored to produce functional proteins, a phenomenon known as the compensatory frameshift.

Results

In this study, we systematically analyzed publicly available viral genome sequences and identified compensatory frameshift events in hundreds of viral protein-coding sequences. Compensatory frameshift events resulted in large-scale amino acid differences between the compensatory frameshift form and the wild type even though their nucleotide sequences were almost identical. Phylogenetic analyses revealed that the evolutionary distance between proteins with and without a compensatory frameshift were significantly overestimated because amino acid mismatches caused by compensatory frameshifts were counted as substitutions. Further, this could cause compensatory frameshift forms to branch in different locations in the protein and nucleotide trees, which may obscure the correct interpretation of phylogenetic relationships between variant viruses.

Conclusions

Our results imply that the compensatory frameshift is one of the mechanisms driving the rapid protein evolution of RNA viruses and potentially assisting their host-range expansion and adaptation.

SUBMITTER: Park D

PROVIDER: S-EPMC8127213 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:UnlabelledHuman immunodeficiency virus (HIV) replication is strongly dependent upon a programmed ribosomal frameshift. Here we investigate the relationships between the thermodynamic stability of the HIV type 1 (HIV-1) RNA frameshift site stem-loop, frameshift efficiency, and infectivity, using pseudotyped HIV-1 and HEK293T cells. The data reveal a strong correlation between frameshift efficiency and local, but not overall, RNA thermodynamic stability. Mutations that modestly increase the local stability of the frameshift site RNA stem-loop structure increase frameshift efficiency 2-fold to 3-fold in cells. Thus, frameshift efficiency is determined by the strength of the thermodynamic barrier encountered by the ribosome. These data agree with previous in vitro measurements, suggesting that there are no virus- or host-specific factors that modulate frameshifting. The data also indicate that there are no sequence-specific requirements for the frameshift site stem-loop. A linear correlation between Gag-polymerase (Gag-Pol) levels in cells and levels in virions supports the idea of a stochastic virion assembly mechanism. We further demonstrate that the surrounding genomic RNA secondary structure influences frameshift efficiency and that a mutation that commonly arises in response to protease inhibitor therapy creates a functional but inefficient secondary slippery site. Finally, HIV-1 mutants with enhanced frameshift efficiencies are significantly less infectious, suggesting that compounds that increase frameshift efficiency by as little as 2-fold may be effective at suppressing HIV-1 replication.ImportanceHIV, like many retroviruses, utilizes a -1 programmed ribosomal frameshift to generate viral enzymes in the form of a Gag-Pol polyprotein precursor. Thus, frameshifting is essential for viral replication. Here, we utilized a panel of mutant HIV strains to demonstrate that in cells, frameshifting efficiency is correlated with the stability of the local thermodynamic barrier to ribosomal translocation. Increasing the stability of the frameshift site RNA increases the frameshift efficiency 2-fold to 3-fold. Mutant viruses with increased frameshift efficiencies have significantly reduced infectivity. These data suggest that this effect might be exploited in the development of novel antiviral strategies.