The A-rich RNA sequences of HIV-1 pol are important for the synthesis of viral cDNA

Caroline P Keating, Melissa K Hill, David James Hawkes, Redmond Patrick Smyth, Catherine Isel, Shu-Yun Le, Ann C Palmenberg, John A Marshall, Roland Marquet, Gary J Nabel, Johnson Mak

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The bias of A-rich codons in HIV-1 pol is thought to be a record of hypermutations in viral genomes that lack biological functions. Bioinformatic analysis predicted that A-rich sequences are generally associated with minimal local RNA structures. Using codon modifications to reduce the amount of A-rich sequences within HIV-1 genomes, we have reduced the flexibility of RNA sequences in pol to analyze the functional significance of these A-rich structurally poor RNA elements in HIV-1 pol. Our data showed that codon modification of HIV-1 sequences led to a suppression of virus infectivity by 5-100-fold, and this defect does not correlate with, viral entry, viral protein expression levels, viral protein profiles or virion packaging of genomic RNA. Codon modification of HIV-1 pol correlated with an enhanced dimer stability of the viral RNA genome, which was associated with a reduction of viral cDNA synthesis both during HIV-1 infection and in a cell free reverse transcription assay. Our data provided direct evidence that the HIV-1 A-rich pol sequence is not merely an evolutionary artifact of enzyme-induced hypermutations, and that HIV-1 has adapted to rely on A-rich RNA sequences to support the synthesis of viral cDNA during reverse transcription, highlighting the utility of using structurally poor RNA domains in regulating biological process.
Original languageEnglish
Pages (from-to)945 - 956
Number of pages11
JournalNucleic Acids Research
Publication statusPublished - 2009

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