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      Genomic HIV RNA Induces Innate Immune Responses through RIG-I-Dependent Sensing of Secondary-Structured RNA

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          Abstract

          Background

          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.

          Methods/Principal Findings

          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.

          Conclusions/Significance

          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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          Most cited references 27

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          Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA.

          Interferons (IFNs) are critical for protection from viral infection, but the pathways linking virus recognition to IFN induction remain poorly understood. Plasmacytoid dendritic cells produce vast amounts of IFN-alpha in response to the wild-type influenza virus. Here, we show that this requires endosomal recognition of influenza genomic RNA and signaling by means of Toll-like receptor 7 (TLR7) and MyD88. Single-stranded RNA (ssRNA) molecules of nonviral origin also induce TLR7-dependent production of inflammatory cytokines. These results identify ssRNA as a ligand for TLR7 and suggest that cells of the innate immune system sense endosomal ssRNA to detect infection by RNA viruses.
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            Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.

            Treatment of infected patients with ABT-538, an inhibitor of the protease of human immunodeficiency virus type 1 (HIV-1), causes plasma HIV-1 levels to decrease exponentially (mean half-life, 2.1 +/- 0.4 days) and CD4 lymphocyte counts to rise substantially. Minimum estimates of HIV-1 production and clearance and of CD4 lymphocyte turnover indicate that replication of HIV-1 in vivo is continuous and highly productive, driving the rapid turnover of CD4 lymphocytes.
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              Architecture and Secondary Structure of an Entire HIV-1 RNA Genome

              Single-stranded RNA viruses encompass broad classes of infectious agents and cause the common cold, cancer, AIDS, and other serious health threats. Viral replication is regulated at many levels, including using conserved genomic RNA structures. Most potential regulatory elements within viral RNA genomes are uncharacterized. Here we report the structure of an entire HIV-1 genome at single nucleotide resolution using SHAPE, a high-throughput RNA analysis technology. The genome encodes protein structure at two levels. In addition to the correspondence between RNA and protein primary sequences, a correlation exists between high levels of RNA structure and sequences that encode inter-domain loops in HIV proteins. This correlation suggests RNA structure modulates ribosome elongation to promote native protein folding. Some simple genome elements previously shown to be important, including the ribosomal gag-pol frameshift stem-loop, are components of larger RNA motifs. We also identify organizational principles for unstructured RNA regions. Highly used splice acceptors lie in unstructured motifs and hypervariable regions are sequestered from flanking genome regions by stable insulator helices. These results emphasize that the HIV-1 genome and, potentially, many coding RNAs are punctuated by numerous previously unrecognized regulatory motifs and that extensive RNA structure may constitute an additional level of the genetic code.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                3 January 2012
                : 7
                : 1
                Affiliations
                [1 ]Department of Infectious Diseases, Aarhus University Hospital - Skejby, Aarhus, Denmark
                [2 ]Unit of Excellence for Immunotoxicology, Finnish Institute of Occupational Health, Helsinki, Finland
                [3 ]Department of Biomedicine, University of Aarhus, Aarhus, Denmark
                [4 ]AIDS and Cancer Virus Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland, United States of America
                Institut Pasteur Korea, Republic of Korea
                Author notes

                Conceived and designed the experiments: RKB JM SRP THM. Performed the experiments: RKB JM JR ED SS KAH. Analyzed the data: RKB JM SRP THM. Contributed reagents/materials/analysis tools: RJG CSL LO SM. Wrote the paper: RKB THM.

                Article
                PONE-D-11-12168
                10.1371/journal.pone.0029291
                3250430
                22235281
                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
                Page count
                Pages: 10
                Categories
                Research Article
                Biology
                Biophysics
                Nucleic Acids
                RNA
                Immunology
                Immunity
                Microbiology
                Immunity
                Molecular Cell Biology
                Nucleic Acids
                RNA
                Medicine
                Clinical Immunology
                Immunity
                Infectious Diseases
                Viral Diseases
                HIV
                Physics
                Biophysics
                Nucleic Acids
                RNA

                Uncategorized

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