A highly defective HIV-1 group O provirus: evidence for the role of local sequence determinants in G-->A hypermutation during negative-strand viral DNA synthesis.
The sequence of 2350 nucleotides in the env and IN regions of a group O HIV-1 genome which is hypermutated throughout its entirety was compared to the equivalent sequence of a nonhypermutated genome from the same isolate. Almost 30% of G residues were affected by G-->A transitions. As previously reported, transitions occurred mainly at GpA and GpG dinucleotides, with a marked preference for changes of the 5'-proximal G residues in poly(G) stretches. Inspection of the sequences around the hypermutation sites revealed no bias when the mutation was at the 5' G residue of a GpG dinucleotide. In contrast, a preferred context for hypermutation at the 3' G (or at single G residues) could be defined. In addition to a preference for A residues immediately downstream of hypermutated 3' G residues, C residues were underrepresented in these positions. The observed context fits well with a model whereby G-->A mutation occurs by a combination of dislocation mutagenesis at GpA dinucleotides and direct misincorporation of dTTP at the 5' G of GpG dinucleotides. Furthermore, both runs of six G residues present in the polypurine tracts (PPTs) had escaped hypermutation, despite the fact that 95% of runs of three G residues contained at least one G-->A transition. This finding suggests that genomes with hypermutated PPT motifs had been selected against and provides direct evidence that hypermutation occurs during negative-strand DNA synthesis.
Borman
A M
AM
Oncologie Virale (INSERM URA 1157), Département Sida et Rétrovirus, Institut Pasteur, Paris, France.
Quillent
C
C
Charneau
P
P
Kean
K M
KM
Clavel
F
F
D001483:Base Sequence; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004279:DNA, Viral / Q000096:biosynthesis / Q000235:genetics*; D015752:Genes, env / Q000235:genetics; D015751:Genes, pol / Q000235:genetics; D016679:Genome, Viral; D006150:Guanine Nucleotides / Q000235:genetics; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D017354:Point Mutation / Q000235:genetics; D011068:Poly G / Q000235:genetics; D011533:Proviruses / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
D004279:DNA, Viral; D006150:Guanine Nucleotides; D011068:Poly G