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HIV-1 tolerates changes in A-count in a small segment of the pol gene.

HIV-1 tolerates changes in A-count in a small segment of the pol gene.
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Klaver B, van der Velden Y, van Hemert F, van der Kuyl AC, Berkhout B,


Klaver B, van der Velden Y, van Hemert F, van der Kuyl AC, Berkhout B, (click to view)

Klaver B, van der Velden Y, van Hemert F, van der Kuyl AC, Berkhout B,

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Retrovirology 2017 09 0514(1) 43 doi 10.1186/s12977-017-0367-0

Abstract
BACKGROUND
The HIV-1 RNA genome has a biased nucleotide composition with a surplus of As. Several hypotheses have been put forward to explain this striking phenomenon, but the A-count of the HIV-1 genome has thus far not been systematically manipulated. The reason for this reservation is the likelihood that known and unknown sequence motifs will be affected by such a massive mutational approach, thus resulting in replication-impaired virus mutants. We present the first attempt to increase and decrease the A-count in a relatively small polymerase (pol) gene segment of HIV-1 RNA.

RESULTS
To minimize the mutational impact, a new mutational approach was developed that is inspired by natural sequence variation as present in HIV-1 isolates. This phylogeny-instructed mutagenesis allowed us to create replication-competent HIV-1 mutants with a significantly increased or decreased local A-count. The local A-count of the wild-type (wt) virus (40.2%) was further increased to 46.9% or reduced to 31.7 and 26.3%. These HIV-1 variants replicate efficiently in vitro, despite the fact that the pol changes cause a quite profound move in HIV-SIV sequence space.

CONCLUSIONS
Extrapolating these results to the complete 9 kb RNA genome, we may cautiously suggest that the A-rich signature does not have to be maintained. This survey also provided clues that silent codon changes, in particular from G-to-A, determine the subtype-specific sequence signatures.

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