Bernard, Mark A.Zhao, HuiYue, Simon C.Anandaiah, AshaKoziel, HenryTachado, Souvenir D.2014-10-012014Bernard, Mark A., Hui Zhao, Simon C. Yue, Asha Anandaiah, Henry Koziel, and Souvenir D. Tachado. 2014. “Novel HIV-1 MiRNAs Stimulate TNFα Release in Human Macrophages via TLR8 Signaling Pathway.” PLoS ONE 9 (9): e106006. doi:10.1371/journal.pone.0106006. http://dx.doi.org/10.1371/journal.pone.0106006.1932-6203http://nrs.harvard.edu/urn-3:HUL.InstRepos:12987304Purpose 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. Conclusion: 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.en-USBiology and life sciencesBiochemistryDNADNA amplificationRNAMessenger RNAMicroRNAsSmall interfering RNAsCell BiologyCellular TypesAnimal CellsBlood CellsWhite Blood CellsMacrophagesImmune CellsImmunologyClinical ImmunologyImmunopathologyImmune ResponseInflammationMicrobiologyMedical MicrobiologyMicrobial PathogensViral PathogensImmunodeficiency VirusesHIV-1OrganismsVirusesJournal Article2014-10-0110.1371/journal.pone.0106006