Abstract

Hypermutation involving excessive G-to-A substitutions in the dinucleotide context GA or GG is common among the lentiviruses and results in multiple stop codons across the genome. Hypermutated viruses have been associated with slower disease progression and might reflect an antiviral cell-defense mechanism. However, it is unclear how soon G-to-A substitutions are generated after infection and whether they occur randomly along the genome. In this report we describe for the first time hypermutated sequences detected at delivery and in the first weeks of life, which suggests that they could be either generated in utero and soon after birth and/or vertically transmitted. Hypermutated C2-C5 env clones were harbored in 13.2% of 243 infants and 18.6% of 199 mothers. A lower extent of hypermutation was found in infants than in mothers (Fisher's exact p = 0.034), but there was no relationship between the percent hypermutated Gs and viral subtype or transmission status of the mother. Analyses of six hypermutated full-length HIV-1 clones showed that although all genes could be affected by G-to-A substitutions, there was a significant drop in the extent of hypermutation between the central polypurine tract and the beginning of env, indicating that hypermutation across the HIV-1 genome might occur in a specific pattern. The genomic regions most affected by hypermutation were pol and env while both polypurine tracts remained unaffected. A better understanding of the mechanism of hypermutation may reveal novel virus-host interactions that could be targeted in drug development.