G-]A HYPERMUTATION OF THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 GENOME - EVIDENCE FOR DCTP POOL IMBALANCE DURING REVERSE TRANSCRIPTION

The quasispecies model for RNA viruses predicts the existence of a rep lication 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 bo th GpG and GpA dinucleotide contexts. Transitions in GpG preferentiall y 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 circumsta nces may be related by the local dCTP substrate concentration. An in v itro elongation assay shows that primer/template dislocation is more f requent for the human immunodeficiency virus type 1 reverse transcript ase than for murine or avian retroviral enzymes. Taken together these data suggest that G --> A hypermutation is an example of induced mutat ion whereby the viral reverse transcriptase is forced into making erro rs by imbalances in the intracellular dCTP concentration.