ADENOVIRUS SEROTYPE EVOLUTION IS DRIVEN BY ILLEGITIMATE RECOMBINATIONIN THE HYPERVARIABLE REGIONS OF THE HEXON PROTEIN

The origin of AIDS-associated adenoviruses (AV 43-AV 49) was investiga ted by examining evolutionary relationships among 18 serologically rel ated subgenus D serotypes and 3 intermediates and determining the muta tion rate of a single serotype, AV 48, among clinical isolates from AI DS patients over a 6-year period. Nucleotide sequence of conserved and seven hypervariable regions (HVRs) of the hexon protein, the pVI core protein signal peptide, and noncoding region between the two genes wa s determined. Among AV 48 isolates the base misincorporation rate was 3.2 per 10,000 bases over 6 years. A 6-bp deletion occurred in one iso late between short direct repeats in HVR 7, Among subgenus D serotypes mutation rates were extremely low in the pVI peptide, the 5' hexon no ncoding region, and first 187 bases of hexon protein. Small 2-and 3-bp deletions between short direct repeats in a polypurine stretch in the noncoding region occurred in 3 strains, Mutation increased with proxi mity to the HVRs. Within HVR 1, 2, 4, 5, and 7 variability consisted o f extensive intrachromosomal illegitimate recombination, including del etions between short direct repeats, insertions and duplications in re petitive polypurine stretches, and numerous base substitutions. All se rotypes and intermediates differed by at least one illegitimate recomb ination event, with one exception. We conclude that AV serotype evolut ion is driven by illegitimate recombination events (antigenic shift), concommitant with single base mutation (antigenic drift), and that the HVRs are ''hot spots'' for both. These events could be explained by s lippage-misalignment of the AV DNA polymerase in repetitive polypurine stretches during single-strand DNA replication. This mutability in th e suriace regions of the major viral coat protein confers a distinctsu rvival advantage to this family of viruses. (C) 1996 Academic Press, I nc.