The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1

1005 Human immunodeficiency virus (HIV) introduces its single-stranded RNA (ssRNA) genome into a cell in the reverse-transcription complex, which matures into the preintegration complex. This complex delivers reverse-transcribed HIV DNA to the nucleus for chromosomal integration. Few copies of HIV DNA integrate, leaving behind HIV DNA in the cytosol to be cleared by host enzymes. Although nucleic acids in the reverse-transcription complex might be shielded from nucleic acid sensors, viral DNA in the preintegration complex is accessible to exogenous endonucleases1 and thus is potentially accessible to cytosolic sensors of innate immunity. The endoplasmic reticulum–associated SET complex, which contains three DNases (APE1, NM23-H1 and TREX1) and other proteins (SET, pp32 and HMGB2), binds to the HIV preintegration complex and protects the integrase-activated DNA ends from self attack in suicidal autointegration2. Suppressing the expression of any gene encoding a molecule of the SET complex increases autointegration and interferes with chromosomal integration. TREX1 is the most abundant 3′-5′ DNase in cells2. Treatment with TREX1-specific small interfering RNA (siRNA) inhibits HIV replication more profoundly than do siRNAs specific for other SET complex components, decreasing viral production by a log2. TREX1 mutations are associated with inflammatory and autoimmune diseases, including Aicardi-Goutieres syndrome, chilblain lupus, and systemic lupus erythematosus, some of which have more type I interferon3–5. TREX1 binds to transfected immunostimulatory DNA, and Trex1−/− cells accumulate cytoplasmic DNA derived from endogenous retroelements, which activates interferon expression dependent on interferon-regulatory factor 3 (IRF3)6–8. Like HIV, endogenous retroelements undergo cytoplasmic reverse transcription. We therefore investigated whether HIV might use TREX1 to avoid triggering antiviral innate immunity.

[1]  Pengyuan Yang,et al.  The cytosolic nucleic acid sensor LRRFIP1 mediates the production of type I interferon via a β-catenin-dependent pathway , 2010, Nature Immunology.

[2]  Ashley T. Haase,et al.  Targeting early infection to prevent HIV-1 mucosal transmission , 2010, Nature.

[3]  V. Hornung,et al.  Intracellular DNA recognition , 2010, Nature Reviews Immunology.

[4]  S. Akira,et al.  HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses , 2009, Nature.

[5]  G. Barber,et al.  STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity , 2009, Nature.

[6]  Zhijian J. Chen,et al.  RNA Polymerase III Detects Cytosolic DNA and Induces Type I Interferons through the RIG-I Pathway , 2009, Cell.

[7]  V. Hornung,et al.  RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III–transcribed RNA intermediate , 2009, Nature Immunology.

[8]  Xiaoping Zhou,et al.  ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization , 2009, Proceedings of the National Academy of Sciences.

[9]  Qiang Sun,et al.  Ubiquitin-Regulated Recruitment of IκB Kinase ε to the MAVS Interferon Signaling Adapter , 2009, Molecular and Cellular Biology.

[10]  J. Tschopp,et al.  Innate Immunity: Cytoplasmic DNA Sensing by the AIM2 Inflammasome , 2009, Current Biology.

[11]  J. Lieberman,et al.  The SET Complex Acts as a Barrier to Autointegration of HIV-1 , 2009, PLoS pathogens.

[12]  L. Gehrke,et al.  Nucleotide Sequences and Modifications That Determine RIG-I/RNA Binding and Signaling Activities , 2009, Journal of Virology.

[13]  Benjamin A. Garcia,et al.  Chromatin-Specific Remodeling by HMGB1 and Linker Histone H1 Silences Proinflammatory Genes during Endotoxin Tolerance , 2009, Molecular and Cellular Biology.

[14]  T. Hollis,et al.  The TREX1 Double-stranded DNA Degradation Activity Is Defective in Dominant Mutations Associated with Autoimmune Disease* , 2008, Journal of Biological Chemistry.

[15]  J. Church.  Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen , 2008, Pediatrics.

[16]  Y. Li,et al.  The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. , 2008, Immunity.

[17]  G. Barber,et al.  STING an Endoplasmic Reticulum Adaptor that Facilitates Innate Immune Signaling , 2008, Nature.

[18]  T. Heidmann,et al.  Trex1 Prevents Cell-Intrinsic Initiation of Autoimmunity , 2008, Cell.

[19]  D. Barnes,et al.  Trex1 Exonuclease Degrades ssDNA to Prevent Chronic Checkpoint Activation and Autoimmune Disease , 2007, Cell.

[20]  J. Lieberman,et al.  Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus , 2007, Nature Genetics.

[21]  K. Honda,et al.  DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response , 2007, Nature.

[22]  A. Engelman,et al.  LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. , 2007, Genes & development.

[23]  J. Lieberman,et al.  A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus , 2007, Journal of Molecular Medicine.

[24]  A. Engelman,et al.  Wild-Type Levels of Human Immunodeficiency Virus Type 1 Infectivity in the Absence of Cellular Emerin Protein , 2006, Journal of Virology.

[25]  D. Barnes,et al.  Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus , 2006, Nature Genetics.

[26]  J. Lifson,et al.  Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. , 2005, The Journal of clinical investigation.

[27]  Ralf Bartenschlager,et al.  Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus , 2005, Nature.

[28]  Osamu Takeuchi,et al.  IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction , 2005, Nature Immunology.

[29]  Z. Zhai,et al.  VISA Is an Adapter Protein Required for Virus-Triggered IFN-β Signaling , 2005 .

[30]  Hideo Negishi,et al.  IRF-7 is the master regulator of type-I interferon-dependent immune responses , 2005, Nature.

[31]  Angelika Pedal,et al.  SIRT1 Regulates HIV Transcription via Tat Deacetylation , 2005, PLoS biology.

[32]  C. Coban,et al.  Interferon-α induction through Toll-like receptors involves a direct interaction of IRF7 with MyD88 and TRAF6 , 2004, Nature Immunology.

[33]  D. Barnes,et al.  Gene-Targeted Mice Lacking the Trex1 (DNase III) 3′→5′ DNA Exonuclease Develop Inflammatory Myocarditis , 2004, Molecular and Cellular Biology.

[34]  J. Lieberman,et al.  Tumor Suppressor NM23-H1 Is a Granzyme A-Activated DNase during CTL-Mediated Apoptosis, and the Nucleosome Assembly Protein SET Is Its Inhibitor , 2003, Cell.

[35]  Y. Shoenfeld,et al.  HIV and autoimmunity. , 2002, Autoimmunity reviews.

[36]  F. Bushman,et al.  Poly(ADP-Ribose) Polymerase 1 Is Not Strictly Required for Infection of Murine Cells by Retroviruses , 2002, Journal of Virology.

[37]  Michael R. Green,et al.  Inappropriate Gene Activation in FSHD A Repressor Complex Binds a Chromosomal Repeat Deleted in Dystrophic Muscle , 2002, Cell.

[38]  Judy Lieberman,et al.  HMG2 Interacts with the Nucleosome Assembly Protein SET and Is a Target of the Cytotoxic T-Lymphocyte Protease Granzyme A , 2002, Molecular and Cellular Biology.

[39]  Dan J. Mazur,et al.  Identification and Expression of the TREX1 and TREX2 cDNA Sequences Encoding Mammalian 3′→5′ Exonucleases* , 1999, The Journal of Biological Chemistry.

[40]  M. Ptashne,et al.  Chromatin components as part of a putative transcriptional repressing complex. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Sodroski,et al.  CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia , 1997, Nature.

[42]  M. Katze,et al.  Interferon treatment inhibits virus replication in HIV-1- and SIV-infected CD4+ T-cell lines by distinct mechanisms: evidence for decreased stability and aberrant processing of HIV-1 proteins. , 1995, Virology.

[43]  H. Gendelman,et al.  Alpha interferon-induced antiretroviral activities: restriction of viral nucleic acid synthesis and progeny virion production in human immunodeficiency virus type 1-infected monocytes , 1994, Journal of virology.

[44]  E. Coccia,et al.  Specific inhibition of viral protein synthesis in HIV-infected cells in response to interferon treatment. , 1994, The Journal of biological chemistry.

[45]  P. Pitha,et al.  Alpha interferon inhibits early stages of the human immunodeficiency virus type 1 replication cycle , 1992, Journal of virology.

[46]  P. Brown,et al.  A nucleoprotein complex mediates the integration of retroviral DNA. , 1989, Genes & development.

[47]  B. Hirt.  Selective extraction of polyoma DNA from infected mouse cell cultures. , 1967, Journal of molecular biology.

[48]  R. Medzhitov,et al.  Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. , 2006, Immunity.

[49]  Zhijian J. Chen,et al.  Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. , 2005, Cell.

[50]  M. Groot,et al.  A R T I C L E S COSMOLOGY AND GENESIS: THE ROAD TO HARMONY AND THE NEED FOR COSMOLOGICAL ALTERNATIVES , 1992 .

[51]  B. Walker,et al.  HIV-1 infection does not induce tumor necrosis factor-alpha or interferon-beta gene transcription. , 1991, Journal of acquired immune deficiency syndromes.