title: HIV-derived ssRNA binds to TLR8 to induce inflammation-driven macrophage foam cell formation.
abstract: Even though combined anti-retroviral therapy (cART) dramatically improves patient survival, they remain at a higher risk of being afflicted with non-infectious complications such as cardiovascular disease (CVD). This increased risk is linked to persistent inflammation and chronic immune activation. In this study, we assessed whether this complication is related to HIV-derived ssRNAs inducing in macrophages increases in TNFα release through TLR8 activation leading to foam cell formation. HIV ssRNAs induced foam cell formation in monocyte-derived macrophages (MDMs) in a dose-dependent manner. This response was reduced when either endocytosis or endosomal acidification was inhibited by dynasore or chloroquine, respectively. Using a flow cytometry FRET assay, we demonstrated that ssRNAs bind to TLR8 in HEK cells. In MDMs, ssRNAs triggered a TLR8-mediated inflammatory response that ultimately lead to foam cell formation. Targeted silencing of the TLR8 and MYD88 genes reduced foam cell formation. Furthermore, foam cell formation induced by these ssRNAs was blocked by an anti-TNFα neutralizing antibody. Taken together in MDMs, HIV ssRNAs are internalized; bind TLR8 in the endosome followed by endosomal acidification. TLR8 signaling then triggers TNFα release and ultimately leads to foam cell formation. As this response was inhibited by a blocking anti-TNFα antibody, drug targeting HIV ssRNA-driven TLR8 activation may serve as a potential therapeutic target to reduce chronic immune activation and inflammation leading to CVD in HIV+ patients.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine; Department of 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; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Xinbing
authors.initials: X
authors.lastname: Han
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Sonya
authors.initials: S
authors.lastname: Inderbitzin
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Ifunanya
authors.initials: I
authors.lastname: Agbim
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine; Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, United States of America; From Department of Respiratory Medicine, The Second Hospital of Shanxi Medical University, Taiyuan, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine; Department of 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; Department of 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: D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002738:Chloroquine / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006678:HIV / Q000737:chemistry*; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D061251:Primary Cell Culture; D011485:Protein Binding / Q000187:drug effects; D012367:RNA, Viral / Q000494:pharmacology*; D015398:Signal Transduction; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D006835:Hydrazones; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D012367:RNA, Viral; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; D002738:Chloroquine
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