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. 2012;7(4):e33502.
doi: 10.1371/journal.pone.0033502. Epub 2012 Apr 18.

The biased nucleotide composition of HIV-1 triggers type I interferon response and correlates with subtype D increased pathogenicity

Nicolas Vabret  1 , Marc Bailly-Bechet, Valérie Najburg, Michaela Müller-Trutwin, Bernard Verrier, Frédéric Tangy
Affiliations

The biased nucleotide composition of HIV-1 triggers type I interferon response and correlates with subtype D increased pathogenicity

Nicolas Vabret et al. PLoS One. 2012.

Abstract

The genome of human immunodeficiency virus (HIV) has an average nucleotide composition strongly biased as compared to the human genome. The consequence of such nucleotide composition on HIV pathogenicity has not been investigated yet. To address this question, we analyzed the role of nucleotide bias of HIV-derived nucleic acids in stimulating type-I interferon response in vitro. We found that the biased nucleotide composition of HIV is detected in human cells as compared to humanized sequences, and triggers a strong innate immune response, suggesting the existence of cellular immune mechanisms able to discriminate RNA sequences according to their nucleotide composition or to detect specific secondary structures or linear motifs within biased RNA sequences. We then extended our analysis to the entire genome scale by testing more than 1300 HIV-1 complete genomes to look for an association between nucleotide composition of HIV-1 group M subtypes and their pathogenicity. We found that subtype D, which has an increased pathogenicity compared to the other subtypes, has the most divergent nucleotide composition relative to the human genome. These data support the hypothesis that the biased nucleotide composition of HIV-1 may be related to its pathogenicity.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Most HIV-1 genes are divergent from human coding sequences.
The distribution of human coding sequences is represented according to their length (log scale) and nucleotidic divergence, as measured by the Chi-square distance relative to average composition of all human coding sequences. The colored background shows the density of human coding sequences as indicated on the z-scale. Black dots represent either single HIV-1 genes or the entire HIV-1 genome. Note the distinguishable positions of the gag, pol, env and vpu genes.
Figure 2
Figure 2. Humanization of HIV-1 genes strongly reduces their ability to induce IFN-α/β.
(A) Type-I interferon stimulation was measured as the ISRE-dependant expression of luciferase activity in HEK 293 T cells upon transient transfection of HIV-1-derived RNA molecules. The ISRE reporter activity is the ratio of firefly luciferase activity to control renilla luciferase activity in triplicate experiments. In vitro transcribed RNA molecules corresponding to the wild type sequence of the three HIV-1 major genes induced a strong response while their humanized version induced a tenfold lower response. (B) Nucleotide composition of HIV-1 RNA fragments expressed as the A/C/G/U frequencies.
Figure 3
Figure 3. The nucleotidic divergence of HIV-1 RNA fragments correlates with their ability to stimulate IFN-α/β.
A) The black line shows the nucleotide divergence of HIV-1 compared to human genome, as measured by a Chi-square distance in a 500 bp sliding window along the HIV-1 hxb2 genome. The individual contributions of A, C, G, and U nucleotides to this divergence are shown respectively in red, blue, yellow and green. The HIV-1 genome map is schematically represented above the figure. B) Histogram represents the ISRE reporter activity as the ratio of firefly luciferase activity to control renilla luciferase activity determined in HEK 293 T cells cotransfected with HIV-1 RNA fragments and pISRE-Luc reporter. C) Correlation between the nucleotide divergence (x-axis) and the luciferase activation (y-axis) of the 38 RNA fragments from HIV-1 hxb2 genome. Each point corresponds to the average of four replicates and the correlation coefficient was computed only on these averages to not artefactually lower the p-value.
Figure 4
Figure 4
. Overlapping RNA fragments covering the entire genome of HIV-1 hxb2 . PCR fragments of approximately 500 bp, with overlaps of 250 bp, and covering the entire genome of HIV-1 hxb2 were in vitro transcribed with T7 RNA polymerase into a set of uncapped and unpolyadenylated RNA fragments. After purification RNA fragments were migrated on Agilent-2100 Small RNA chips. A ladder on the left indicates the size in nucleotides.
Figure 5
Figure 5. HIV-1 subtype D has the most divergent sequence.
Boxplots show the median and dispersion of the nucleotide divergence of individual HIV-1 genomes from different subtypes to the average of human coding sequences. Red stars indicate that D subtype is significantly more divergent than other subtypes (p = 2×10−6 ANOVA test, p = 5.8×10−6 Student t-test, p = 2.8×10−7 Wilcoxon test). The random 10 kb column shows the median and standard deviation of the divergence between 10 kb of random human coding sequences and the average of all human coding sequences; 95% of the points have a divergence below 0.03, and less than 1% of the points are above 0.05, ie comparable to HIV divergence. Standard deviation gives a natural scale of variation to the graph. These data were not used in the statistical procedure to compare subtypes.
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