Changes in codon-pair bias of human immunodeficiency virus type 1 have profound effects on virus replication in cell culture
Open Access
- 25 July 2013
- journal article
- Published by Springer Science and Business Media LLC in Retrovirology
- Vol. 10 (1), 78
- https://doi.org/10.1186/1742-4690-10-78
Abstract
Background Human immunodeficiency virus type 1 (HIV-1) has a biased nucleotide composition different from human genes. This raises the question of how evolution has chosen the nucleotide sequence of HIV-1 that is observed today, or to what extent the actual encoding contributes to virus replication capacity, evolvability and pathogenesis. Here, we applied the previously described synthetic attenuated virus engineering (SAVE) approach to HIV-1. Results Using synonymous codon pairs, we rationally recoded and codon pair–optimized and deoptimized different moieties of the HIV-1 gag and pol genes. Deoptimized viruses had significantly lower viral replication capacity in MT-4 and peripheral blood mononuclear cells (PBMCs). Varying degrees of ex vivo attenuation were obtained, depending upon both the specific deoptimized region and the number of deoptimized codons. A protease optimized virus carrying 38 synonymous mutations was not attenuated and displayed a replication capacity similar to that of the wild-type virus in MT-4 cells and PBMCs. Although attenuation is based on several tens of nucleotide changes, deoptimized HIV-1 reverted to wild-type virulence after serial passages in MT-4 cells. Remarkably, no reversion was observed in the optimized virus. Conclusion These data demonstrate that SAVE is a useful strategy to phenotypically affect the replicative properties of HIV-1.Keywords
This publication has 37 references indexed in Scilit:
- Identification of two functionally redundant RNA elements in the coding sequence of poliovirus using computer-generated designProceedings of the National Academy of Sciences of the United States of America, 2012
- Transcriptional and Posttranscriptional Regulation of HIV-1 Gene ExpressionCold Spring Harbor Perspectives in Medicine, 2011
- Computationally designed adeno-associated virus (AAV) Rep 78 is efficiently maintained within an adenovirus vectorProceedings of the National Academy of Sciences of the United States of America, 2011
- Thymidine Analogue Excision and Discrimination Modulated by Mutational Complexes Including Single Amino Acid Deletions of Asp-67 or Thr-69 in HIV-1 Reverse TranscriptaseOnline Journal of Public Health Informatics, 2011
- Synonymous but not the same: the causes and consequences of codon biasNature Reviews Genetics, 2010
- Mechanisms Involved in the Selection of HIV-1 Reverse Transcriptase Thumb Subdomain Polymorphisms Associated with Nucleoside Analogue Therapy FailureAntimicrobial Agents and Chemotherapy, 2010
- Live attenuated influenza virus vaccines by computer-aided rational designNature Biotechnology, 2010
- The A-rich RNA sequences of HIV-1 pol are important for the synthesis of viral cDNANucleic Acids Research, 2008
- Virus Attenuation by Genome-Scale Changes in Codon Pair BiasScience, 2008
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001