The Biased Nucleotide Composition of HIV-1 Triggers Type I Interferon Response and Correlates with Subtype D Increased Pathogenicity

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

doi:10.1371/journal.pone.0033502

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.

Highlights

Without treatment, most individuals infected with human immunodeficiency virus (HIV) will develop AIDS as a consequence of years of chronic and excessive activation of their immune system [1]
Our observation demonstrates that the biased nucleotide composition of HIV synthetic RNA molecules, or its structural consequence, is detected in human cells and triggers a strong innate immune response
Very little is known about the consequences of the biased nucleotide composition of human immunodeficiency viruses on their pathogenicity

Summary

Introduction

Most individuals infected with HIV will develop AIDS as a consequence of years of chronic and excessive activation of their immune system [1]. Viral nucleic acids trigger an antiviral innate immune response in infected cells, which contributes to activating the immune system [4,5,6]. During the acute phase of HIV infection, pDCs are the main producers of IFN-a/b. They recognize viral ssRNA via TLR7, and dsDNA via TLR9 [14,15]. This antiviral response contributes to containing the acute infection. A recent study reported that in chronically HIV-infected patients IFNa colocalized only with few pDCs, but rather with other TLR7 negative cells [16]

Methods

Results

Conclusion