title: Increased cell-free mitochondrial DNA is a marker of ongoing inflammation and better neurocognitive function in virologically suppressed HIV-infected individuals.
abstract: Cell-free mitochondrial DNA (mtDNA) is a highly immunogenic molecule that is associated with several inflammatory conditions and with neurocognitive impairment during untreated HIV infection. Here, we investigate how cell-free mtDNA in cerebrospinal fluid (CSF) is associated with inflammation, neuronal damage, and neurocognitive functioning in the context of long-term suppressive antiretroviral therapy (ART). We quantified the levels of cell-free mtDNA in the CSF from 41 HIV-infected individuals with completely suppressed HIV RNA levels in blood plasma (<50 copies/mL) by droplet digital PCR. We measured soluble CD14, soluble CD163, interferon γ-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), neopterin, and neurofilament light chain (NFL) by immunoassays in CSF supernatant or blood plasma. Higher levels of mtDNA in CSF were associated with higher levels of MCP-1 (r = 0.56, p < 0.01) in CSF and TNF-α (r = 0.43, p < 0.01) and IL-8 (r = 0.44, p < 0.01) in blood plasma. Subjects with a previous diagnosis of AIDS showed significantly higher levels of mtDNA (p < 0.01) than subjects without AIDS. The associations between mtDNA and MCP-1 in CSF and TNF-α in blood remained significant after adjusting for previous diagnosis of AIDS (p < 0.01). Additionally, higher levels of mtDNA were associated with a lower CD4 nadir (r = -0.41, p < 0.01) and lower current CD4% (r = -0.34, p = 0.03). Paradoxically, higher levels of mtDNA in CSF were significantly associated with better neurocognitive performance (r = 0.43, p = 0.02) and with less neuronal damage (i.e. lower NFL). Higher cell-free mtDNA is associated with inflammation during treated HIV infection, but the impact on neurocognitive functioning and neuronal damage remains unclear and may differ in the setting of suppressive ART.
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA. joperez@ucsd.edu.
authors.forename: Josué
authors.identifier: 0000-0002-3514-8641
authors.initials: J
authors.lastname: Pérez-Santiago
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.
authors.forename: Michelli F
authors.initials: MF
authors.lastname: De Oliveira
authors.affiliation: Western Michigan University, Kalamazoo, MI, USA.
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Var
authors.affiliation: Washington University, St. Louis, MI, USA.
authors.forename: Tyler R C
authors.initials: TRC
authors.lastname: Day
authors.affiliation: University of Houston, Houston, TX, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Woods
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Gianella
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.|Veterans Administration San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Sanjay R
authors.initials: SR
authors.lastname: Mehta
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000097:blood / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000097:blood / Q000235:genetics; D000998:Antiviral Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D018932:Chemokine CCL2 / Q000134:cerebrospinal fluid / Q000235:genetics; D054357:Chemokine CXCL10 / Q000097:blood / Q000235:genetics; D003071:Cognition; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy; D004272:DNA, Mitochondrial / Q000134:cerebrospinal fluid*; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006678:HIV / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D015658:HIV Infections / Q000134:cerebrospinal fluid / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy; D006801:Humans; D016209:Interleukin-8 / Q000097:blood / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D012367:RNA, Viral / Q000097:blood*; D011956:Receptors, Cell Surface / Q000097:blood / Q000235:genetics; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000998:Antiviral Agents; D015415:Biomarkers; C111835:CCL2 protein, human; D000098902:CD163 Antigen; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D004272:DNA, Mitochondrial; D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha
keywords: Inflammation; Neurocognitive performance; Neurodegeneration; ddPCR; mtDNA