Impact of Synonymous Genome Recoding on the HIV Life Cycle

Abstract

Synonymous mutations within protein coding regions introduce changes in DNA or messenger (m) RNA, without mutating the encoded proteins. Synonymous recoding of virus genomes has facilitated the identification of previously unknown virus biological features. Moreover, large-scale synonymous recoding of the genome of human immunodeficiency virus type 1 (HIV-1) has elucidated new antiviral mechanisms within the innate immune response, and has improved our knowledge of new functional virus genome structures, the relevance of codon usage for the temporal regulation of viral gene expression, and HIV-1 mutational robustness and adaptability. Continuous improvements in our understanding of the impacts of synonymous substitutions on virus phenotype – coupled with the decreased cost of chemically synthesizing DNA and improved methods for assembling DNA fragments – have enhanced our ability to identify potential HIV-1 and host factors and other aspects involved in the infection process. In this review, we address how silent mutagenesis impacts HIV-1 phenotype and replication capacity. We also discuss the general potential of synonymous recoding of the HIV-1 genome to elucidate unknown aspects of the virus life cycle, and to identify new therapeutic targets.

Synonymous Codon Pair Recoding of the HIV-1 env Gene Affects Virus Replication Capacity

“…Codon pair deoptimization has been widely used to generate attenuated viruses [ 1 , 2 , 14 ], including HIV-1 [ 6 , 9 , 10 ]. We previously demonstrated that codon pair deoptimization of the HIV-1 gag and pol genes strongly compromises virus replication capacity and viability [ 9 , 10 ].…”

“…HIV-1 is no exception, with its genome displaying a significantly lower than expected number of CpGs [ 24 ]. Several studies demonstrate that increasing CpG frequencies have negative effects on HIV-1 fitness, as previously reviewed [ 6 ]. HIV-1 env CpG dinucleotide suppression reportedly enables the virus to evade inhibition by ZAP in MT-4 cells [ 11 ].…”

“…Synonymous genome-wide recoding enables the synthetic generation of various small-genome viruses with modified phenotypes and biological properties. In the context of human immunodeficiency virus type 1 (HIV-1), synonymous recoding has elucidated new antiviral mechanisms within the innate immune response and improved our knowledge of new functional virus genome structures [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. However, the mechanism underlying the alteration of virus phenotype through genome synonymous recoding has not yet been elucidated.…”

“…HIV-1 mimics the CpG dinucleotide suppression of its human host [ 6 ]. Recent data suggest that the zinc-finger antiviral protein (ZAP) may be a driving force behind the CpG dinucleotide suppression in HIV-1 [ 11 ].…”

The Expression Level of HIV-1 Vif Is Optimized by Nucleotide Changes in the Genomic SA1D2prox Region during the Viral Adaptation Process

“…It has been reported that the introduction of numerous synonymous mutations throughout the HIV-1 genome, especially into the central region of the genome, results in replication defects via splicing perturbation [ 56 ]. Several lines of evidence showed that synonymous mutations can affect pivotal biological processes such as RNA splicing, RNA stability, and translation efficiency [ 56 , 57 , 58 ], for review, see [ 59 , 60 ]. This implies that synonymous mutations would be biologically relevant and exposed to selective forces.…”