Genomic HIV RNA induces innate immune responses through RIG-I-dependent sensing of secondary-structured RNA

Department of Infectious Diseases, Aarhus University Hospital-Skejby, Aarhus, Denmark.
PLoS ONE (Impact Factor: 3.23). 01/2012; 7(1):e29291. DOI: 10.1371/journal.pone.0029291
Source: PubMed


Innate immune responses have recently been appreciated to play an important role in the pathogenesis of HIV infection. Whereas inadequate innate immune sensing of HIV during acute infection may contribute to failure to control and eradicate infection, persistent inflammatory responses later during infection contribute in driving chronic immune activation and development of immunodeficiency. However, knowledge on specific HIV PAMPs and cellular PRRs responsible for inducing innate immune responses remains sparse.
Here we demonstrate a major role for RIG-I and the adaptor protein MAVS in induction of innate immune responses to HIV genomic RNA. We found that secondary structured HIV-derived RNAs induced a response similar to genomic RNA. In primary human peripheral blood mononuclear cells and primary human macrophages, HIV RNA induced expression of IFN-stimulated genes, whereas only low levels of type I IFN and tumor necrosis factor α were produced. Furthermore, secondary structured HIV-derived RNA activated pathways to NF-κB, MAP kinases, and IRF3 and co-localized with peroxisomes, suggesting a role for this organelle in RIG-I-mediated innate immune sensing of HIV RNA.
These results establish RIG-I as an innate immune sensor of cytosolic HIV genomic RNA with secondary structure, thereby expanding current knowledge on HIV molecules capable of stimulating the innate immune system.

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Available from: Carsten Schade Larsen, Oct 09, 2015
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    • "Moreover, interaction between HIV gp120 and DC-SIGN induces phosphorylation of NF-κB, and this signal from DC-SIGN appears to be required for elongation of viral transcripts and hence for synthesis of complete transcripts and productive infection [44]. Within the cytoplasm, RIG-I has been proposed to recognize HIV genomic ssRNA [45], [46]. In addition, the viral capsid constitutes a PAMP and is recognized by several cytosolic sensors, including Cyclophilin A and TRIM5α [47], [48]. "
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    • "During HIV infection, PRR activation can be mediated by pathogen-associated molecular patterns (PAMPs) directly derived from HIV, such as genomic HIV RNA recognized by endosomal TLR7/8 [24] or cytosolic RLRs [2] [10]. In addition, reverse transcription products, such as single-stranded DNA, may be recognized by cytosolic DNA sensors [23] [25]. "
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    • "Monomeric HIV-1 RNA was an even better inducer of RIG-I than dimeric HIV-1 RNA [100]. Secondary structures in the viral ssRNA such as the TAR hairpin are better inducers of cytokine expression than HIV-1 RNA oligos without (predicted) extensive secondary structure [101]. However, RIG-I signaling is efficiently inhibited by the HIV-1 protease that depletes RIG-I from the cytoplasm [100]. "
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