Abstract
We used a multivariate data analysis approach to identify motifs associated with HIV hypermutation by different APOBEC3 enzymes. The analysis showed that APOBEC3G targets G mainly within GG, TG, TGG, GGG, TGGG and also GGGT. The G nucleotides flanked by a C at the 3′ end (in +1 and +2 positions) were indicated as disfavoured targets by APOBEC3G. The G nucleotides within GGGG were found to be targeted at a frequency much less than what is expected. We found that the infrequent G-to-A mutation within GGGG is not limited to the inaccessibility, to APOBEC3, of poly Gs in the central and 3′polypurine tracts (PPTs) which remain double stranded during the HIV reverse transcription. GGGG motifs outside the PPTs were also disfavoured. The motifs GGAG and GAGG were also found to be disfavoured targets for APOBEC3. The motif-dependent mutation of G within the HIV genome by members of the APOBEC3 family other than APOBEC3G was limited to GA→AA changes. The results did not show evidence of other types of context dependent G-to-A changes in the HIV genome.
Highlights
For many years it was not clear why a proportion of HIV sequences obtained from infected individuals contained G-to-A mutation footprints
Malim et al discovered in 2002 a protein that was responsible for this mutagenic action against many affected HIV sequences [1]
Further studies revealed that this protein belongs to a 7-membered family known as APOBEC3 several of which are known to mutate the HIV genome [2,3,4]
Summary
For many years it was not clear why a proportion of HIV sequences obtained from infected individuals contained G-to-A mutation footprints. Further studies revealed that this protein belongs to a 7-membered family known as APOBEC3 (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3) several of which are known to mutate the HIV genome [2,3,4]. These enzymes are packaged along with the HIV RNA into nascent virions and upon release into a new cell they mutate C to U on the minus strand of HIV. Mono- to tetra-nucleotides are referred to as motifs in this paper
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