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

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 (US)
Pages (from-to)945-956
Number of pages12
JournalNucleic Acids Research
Volume37
Issue number3
DOIs
StatePublished - 2009
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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