Abstract

Synonymous codon pair deoptimization is an efficient strategy for virus attenuation; however, the underlying mechanism remains controversial. Here, we optimized and deoptimized the codon pair bias (CPB) of the human immunodeficiency virus type 1 (HIV-1) envelope (env) gene to investigate the influence of env synonymous CPB recoding on virus replication capacity, as well as the potential mechanism. We found that env CPB deoptimization did not always generate attenuation, whereas CPB optimization attenuated virus replication in MT-4 cells. Furthermore, virus attenuation correlated with reduced Env protein production but not with decreased viral RNA synthesis. Remarkably, in our model, increasing the number of CpG dinucleotides in the 5′ end of env did not reduce the replication capacity of HIV-1. These results indicate that factors other than CPB or CpG content may have impacted the viral fitness of the synonymously recoded study variants. Our findings provide evidence that CPB recoding-associated attenuation can affect translation efficiency. Moreover, we demonstrated that an increased number of CpGs in the 5′ end of HIV-1 env is not always associated with reduced virus replication capacity.

Highlights

  • Large-scale synonymous virus genome recoding has received much attention in recent years because it can be used to generate modified live attenuated vaccines [1,2]

  • We aimed to investigate the effects of human immunodeficiency virus type 1 (HIV-1) envelope codon pair recoding on virus replication capacity and Env protein expression

  • We previously demonstrated that codon pair deoptimization of the HIV-1 gag and pol genes strongly compromises virus replication capacity and viability [9,10]

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Summary

Introduction

Large-scale synonymous virus genome recoding has received much attention in recent years because it can be used to generate modified live attenuated vaccines [1,2]. The mechanism underlying the alteration of virus phenotype through genome synonymous recoding has not yet been elucidated. Codon pair frequencies, termed codon pair bias (CPB), vary among different organisms. Increasing underrepresented codon pairs has led to the generation of highly attenuated viruses of several highly pathogenic human viruses, including poliovirus [14], influenza A virus [15], HIV-1 [10], respiratory syncytial virus (RSV) [16], and dengue virus [17].

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