title: Novel HIV-1 miRNAs stimulate TNFα release in human macrophages via TLR8 signaling pathway.
abstract: OBJECTIVE
  To determine whether HIV-1 produces microRNAs and elucidate whether these miRNAs can induce inflammatory response in macrophages (independent of the conventional miRNA function in RNA interference) leading to chronic immune activation.
  
  
  METHODS
  Using sensitive quantitative Real Time RT-PCR and sequencing, we detected novel HIV-derived miRNAs in the sera of HIV+ persons, and associated with exosomes. Release of TNFα by macrophages challenged with HIV miRNAs was measured by ELISA.
  
  
  RESULTS
  HIV infection of primary alveolar macrophages produced elevated levels of viral microRNAs vmiR88, vmiR99 and vmiR-TAR in cell extracts and in exosome preparations from conditioned medium. Furthermore, these miRNAs were also detected in exosome fraction of sera from HIV-infected persons. Importantly, vmiR88 and vmiR99 (but not vmiR-TAR) stimulated human macrophage TNFα release, which is dependent on macrophage TLR8 expression. These data support a potential role for HIV-derived vmiRNAs released from infected macrophages as contributing to chronic immune activation in HIV-infected persons, and may represent a novel therapeutic target to limit AIDS pathogenesis.
  
  
  CONCLUSIONS
  Novel HIV vmiR88 and vmiR99 are present in the systemic circulation of HIV+ persons and could exhibit biological function (independent of gene silencing) as ligands for TLR8 signaling that promote macrophage TNFα release, and may contribute to chronic immune activation. Targeting novel HIV-derived miRNAs may represent a therapeutic strategy to limit chronic immune activation and AIDS progression.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Bernard
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America; Department of Respiratory Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Yue
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Asha
authors.initials: A
authors.lastname: Anandaiah
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Henry
authors.initials: H
authors.lastname: Koziel
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Souvenir D
authors.initials: SD
authors.lastname: Tachado
mesh_terms: D001482:Base Composition; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D055354:Exosomes / Q000378:metabolism; D020868:Gene Silencing; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism / Q000821:virology; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D008954:Models, Biological; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000235:genetics / Q000494:pharmacology; D034622:RNA Interference; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D015398:Signal Transduction; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D035683:MicroRNAs; D009841:Oligonucleotides; D012367:RNA, Viral; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha