Abstract
The highly conserved trans-acting response element (TAR) present in the RNA genome of human immunodeficiency virus 1 (HIV-1) is a stably folded hairpin structure involved in viral replication. However, TAR is also sensed by viral sensors, leading to antiviral immunity. While high variation in the TAR RNA structure renders the virus replication-incompetent, effects on viral sensing remain unclear. Here, we investigated the role of TAR RNA structure and stability on viral sensing. TAR mutants with deletions in the TAR hairpin that enhanced thermodynamic stability increased antiviral responses. Strikingly, TAR mutants with lower stability due to destabilization of the TAR hairpin also increased antiviral responses without affecting pro-inflammatory responses. Moreover, mutations that affected the TAR RNA sequence also enhanced specific antiviral responses. Our data suggest that mutations in TAR of replication-incompetent viruses can still induce immune responses via viral sensors, hereby underscoring the robustness of HIV-1 RNA sensing mechanisms.
Highlights
All human and simian immunodeficiency virus (HIV and SIV) transcripts carry a hallmark at their 5 end: the structured trans-acting (TAR) RNA response element [1]
We have previously shown that triggering of DDX3 by synthetic abortive HIV type 1 (HIV-1) RNA results in the induction of potent IFNB and interferon-stimulated gene (ISG) transcription, a full antiviral type I interferon (IFN) response capable of limiting HIV-1 replication in vitro [13]
We investigated the effect of variation in the trans-acting response element (TAR) hairpin structure on viral sensing by PRRs
Summary
All human and simian immunodeficiency virus (HIV and SIV) transcripts carry a hallmark at their 5 end: the structured trans-acting (TAR) RNA response element [1]. We introduced mutations within the aborted HIV-1 TAR RNA to study the effect of its thermodynamic stability and RNA structure on viral sensing by PRRs. Notably, we observed that mutations that increased or decreased thermodynamic stability of the TAR hairpin enhanced viral sensing and antiviral immune responses. We observed that mutations that increased or decreased thermodynamic stability of the TAR hairpin enhanced viral sensing and antiviral immune responses These data suggest that viral sensors are able to sense a variety of HIV-1 TAR RNA variants. While virus replication is highly dependent on the integrity and stability of HIV-1 TAR, our study suggests that viral sensors are able to sense many different variations in TAR, underscoring the robustness of the sensing mechanisms for HIV-1 TAR RNA
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