G-->A hypermutation of the human immunodeficiency virus type 1 genome: evidence for dCTP pool imbalance during reverse transcription

Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3092-6. doi: 10.1073/pnas.91.8.3092.

Abstract

The quasispecies model for RNA viruses predicts the existence of a replication error threshold beyond which there is a melting or total loss of sequence information. Retroviral G-->A hypermutation is probably an example. Here it is shown that G-->A transitions may occur in both GpG and GpA dinucleotide contexts. Transitions in GpG preferentially occur via base mispairing at the ends of runs of G residues, whereas G-->A transitions within GpA may result from temporary dislocation of the primer and template strands by a single base. The two circumstances may be related by the local dCTP substrate concentration. An in vitro elongation assay shows that primer/template dislocation is more frequent for the human immunodeficiency virus type 1 reverse transcriptase than for murine or avian retroviral enzymes. Taken together these data suggest that G-->A hypermutation is an example of induced mutation whereby the viral reverse transcriptase is forced into making errors by imbalances in the intracellular dCTP concentration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Composition
  • Base Sequence
  • Deoxycytosine Nucleotides / metabolism
  • HIV Reverse Transcriptase
  • HIV-1 / genetics*
  • Molecular Sequence Data
  • Mutagenesis*
  • Promoter Regions, Genetic
  • Protein Binding
  • RNA-Directed DNA Polymerase / metabolism*
  • Templates, Genetic

Substances

  • Deoxycytosine Nucleotides
  • 2'-deoxycytidine 5'-triphosphate
  • HIV Reverse Transcriptase
  • RNA-Directed DNA Polymerase