Impact of Synonymous Genome Recoding on the HIV Life Cycle.

Ana Jordan-Paiz,Miguel Angel Martínez,Sandra Franco

doi:10.3389/fmicb.2021.606087

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.

Highlights

Despite the relatively recent introduction of human immunodeficiency virus type 1 (HIV-1) within the human population, this virus has already exhibited enormous diversification
Mapping the changes responsible for splicing perturbations in these viruses revealed several RNA sequences that apparently suppressed the use of cryptic or canonical splice sites. These findings indicated complex negative regulation of HIV-1 splicing via RNA elements in various regions of the HIV-1 genome, which maintained a balance between splicing and viral replication (Takata et al, 2018)
By targeting different cellular proteins implicated in mRNA degradation, they revealed that knockdown of a zinc-finger antiviral protein (ZAP) restored the normal replication capacity of CpG-rich HIV-1 variants (Figure 4)

Summary

Introduction

Despite the relatively recent introduction of HIV-1 within the human population, this virus has already exhibited enormous diversification. An interesting and less known application of synonymous nucleotide recoding is to synonymously deoptimize codon usage, codon-pair usage, or dinucleotide frequencies to reduce protein expression and attenuate virus replication capacity, which has been described for several RNA viruses (Figure 3; Martínez et al, 2016, 2019). These findings suggest that viral fitness is altered through nucleotide-dependent modulation of the expression pattern of viral mRNAs. A global silent mutagenesis experiment was performed to identify new cisacting RNA elements in the HIV-1 genome that are important for virus replication (Takata et al, 2018).

Results

Conclusion