Abstract
BackgroundThe human immune proteins APOBEC3G and APOBEC3F (hA3G and hA3F) induce destructive G-to-A changes in the HIV genome, referred to as ‘hypermutation’. These two proteins co-express in human cells, co-localize to mRNA processing bodies and might co-package into HIV virions. Therefore they are expected to also co-mutate the HIV genome. Here we investigate the mutational footprints of hA3G and hA3F in a large population of full genome HIV-1 sequences from naturally infected patients to uniquely identify sequences hypermutated by either or both of these proteins. We develop a method of identification based on the representation of hA3G and hA3F target and product motifs that does not require an alignment to a parental/consensus sequence.ResultsOut of nearly 100 hypermutated HIV-1 sequences only one sequence from the HIV-1 outlier group showed clear signatures of co-mutation by both proteins. The remaining sequences were affected by either hA3G or hA3F.ConclusionUsing a novel method of identification of HIV sequences hypermutated by the hA3G and hA3F enzymes, we report a very low rate of co-mutation of full-length HIV sequences, and discuss the potential mechanisms underlying this.
Highlights
The human immune proteins APOBEC3G and APOBEC3F induce destructive G-to-A changes in the HIV genome, referred to as ‘hypermutation’
The high significance levels of these sequences may imply that they are hypermutated sequences which have been misclassified as normal in the database. Among those sequences tagged as hypermutated in Los Alamos National Laboratory (LANL) database, we identified two sequences that are different from the population of normal HIV-1 sequences at confidence levels less than 50%
Analysis of negative strands Our analysis suggests that motif representation is a useful method for classifying HIV sequences as hypermutated
Summary
The human immune proteins APOBEC3G and APOBEC3F (hA3G and hA3F) induce destructive G-to-A changes in the HIV genome, referred to as ‘hypermutation’ These two proteins co-express in human cells, co-localize to mRNA processing bodies and might co-package into HIV virions. The mechanisms of inhibition proposed for these proteins can be classified as either cytosine deamination-dependent [4] or deamination-independent [5] In the former, one or more hA3G and/or hA3F molecules are trafficked into a nascent virion and are released along with the viral RNA into the cytoplasm of a newly infected cell. During the degradation of the viral RNA, regions of the DNA minus strand remain transiently unpaired These single stranded DNA regions are targeted by hA3G and/or hA3F [6].
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