Lost in translation: implications of HIV-1 codon usage for immune escape and drug resistance.
Synonymous nucleotide substitutions in protein-coding sequences are often regarded as evolutionarily neutral and not subject to selective pressure. However, synonymous codons can sometimes lead to different patterns of amino acid substitution by single nucleotide changes. Based on the deconstruction of the standard genetic code, we propose the term 'quasi-synonymous' to describe codons that specify the same amino acid, but lie on different mutational pathways, and we show that in at least one rapidly evolving organism, HIV-1, quasi-synonymy plays a role in its evolution. We present concrete examples that demonstrate the relevance of codon usage in the development of antiretroviral-drug resistance. In the case of the host immune response, the data indicates that viral evasion is achieved through use of codons that lie on the direct path to escape mutants, and equally, permit rapid reversion to wild-type in the absence of these selective pressures. Quasi-synonymy conditions HIV-1 and, potentially, other rapidly evolving organisms in their exploration of the mutational space.
Kijak
Gustavo H
GH
Henry M. Jackson Foundation for the Advancement of Military Medicine, 1600 East Gude Drive, Rockville, MD 20850, USA. gkijak@hivresearch.org
Currier
Jeffrey R
JR
Tovanabutra
Sodsai
S
Cox
Josephine H
JH
Michael
Nelson L
NL
Wegner
Scott A
SA
Birx
Deborah L
DL
McCutchan
Francine E
FE
D019380:Anti-HIV Agents / Q000494:pharmacology; D003062:Codon / Q000235:genetics*; D024882:Drug Resistance, Viral / Q000235:genetics*; D019143:Evolution, Molecular; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D006801:Humans; D009154:Mutation; D014176:Protein Biosynthesis
D019380:Anti-HIV Agents; D003062:Codon