APOBEC3G and APOBEC3F rarely co-mutate the same HIV genome

Abstract

Background: 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. 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.

Results: Out 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.

Conclusion: Using 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.

Figure 1

The Hotelling’s T² statistics of HIV-1 sequences. There are in total 2917 full genome (> 7000 n.t.) HIV-1 sequences including 2829 nominally normal and 88 nominally hypermutated sequences. The hypermutated sequences are from no. 2830-2917 on the horizontal axis. The filled circles are the nominally normal sequences which are significantly different from the normal HIV-1 population at >> 99.9% confidence levels, thus appear to be hypermutated. The filled triangles are the nominally hypermutated sequences that are significantly different from the normal HIV-1 population at < 50% confidence levels, thus appear to be normal.

Figure 2

The plot of DR_hA3Gversus DR_hA3F of 2917 full genome (>7000 n.t.) HIV-1 sequences. The sequences identified as normal and hypermutated by LANL are shown using black circles and red triangles, respectively. The seven nominally normal sequences with α >> 99.9% (appear outside the 99.9% confidence interval broken line) are shown by filled circles. The two nominally hypermutated sequences with α < 50% are shown by filled triangles. The sequences hypermutated by hA3G appear along the horizontal axis and those affected by hA3F extend along the vertical axis. The sequences co-mutated by hA3G and hA3F locate between these two groups.

Figure 3

The plot of DR_hA3G versus DR_hA3F of a consensus HIV-1 sequence and 19 sequences hypermutated by either hA3G or hA3F. The consensus sequence is shown using a red triangle. Hypermutated sequences by hA3G or hA3F are shown using open and closed rhombuses, respectively. The 99.9% confidence interval of the subtype B HIV-1 population is shown by an oval. The sequences hypermutated by hA3G appear along the horizontal axis, and those hypermutated by hA3F extend along the vertical axis. There is no co-mutated sequence in this dataset.

Figure 4

The plot of DR_hA3G versus DR_hA3F for A) normal HIV-1 population and simulated mutations by B) both hA3G & hA3F (GG-to-AG & GA-to-AA), C) hA3G (GG-to-AG), D) hA3F (GA-to-AA) and E) reverse transcriptase (random G-to-A).