PMID- 27921220 OWN - NLM STAT- MEDLINE DCOM- 20180206 LR - 20181113 IS - 1538-2443 (Electronic) IS - 1355-0284 (Print) IS - 1355-0284 (Linking) VI - 23 IP - 2 DP - 2017 Apr TI - Increased cell-free mitochondrial DNA is a marker of ongoing inflammation and better neurocognitive function in virologically suppressed HIV-infected individuals. PG - 283-289 LID - 10.1007/s13365-016-0497-5 [doi] AB - 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 gamma-induced protein 10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), 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-alpha (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-alpha 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. FAU - Perez-Santiago, Josue AU - Perez-Santiago J AUID- ORCID: 0000-0002-3514-8641 AD - University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA. joperez@ucsd.edu. FAU - De Oliveira, Michelli F AU - De Oliveira MF AD - University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA. FAU - Var, Susanna R AU - Var SR AD - Western Michigan University, Kalamazoo, MI, USA. FAU - Day, Tyler R C AU - Day TRC AD - Washington University, St. Louis, MI, USA. FAU - Woods, Steven P AU - Woods SP AD - University of Houston, Houston, TX, USA. FAU - Gianella, Sara AU - Gianella S AD - University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA. FAU - Mehta, Sanjay R AU - Mehta SR AD - University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA. AD - Veterans Administration San Diego Healthcare System, San Diego, CA, USA. LA - eng GR - R24 AG044325/AG/NIA NIH HHS/United States GR - R25 MH081482/MH/NIMH NIH HHS/United States GR - R01 MH073419/MH/NIMH NIH HHS/United States GR - K23 AI093163/AI/NIAID NIH HHS/United States GR - P30 MH062512/MH/NIMH NIH HHS/United States GR - P30 AI036214/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20161205 PL - United States TA - J Neurovirol JT - Journal of neurovirology JID - 9508123 RN - 0 (Antigens, CD) RN - 0 (Antigens, Differentiation, Myelomonocytic) RN - 0 (Antiviral Agents) RN - 0 (Biomarkers) RN - 0 (CCL2 protein, human) RN - 0 (CD163 antigen) RN - 0 (CXCL10 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (Chemokine CXCL10) RN - 0 (DNA, Mitochondrial) RN - 0 (Interleukin-8) RN - 0 (Lipopolysaccharide Receptors) RN - 0 (RNA, Viral) RN - 0 (Receptors, Cell Surface) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Adult MH - Antigens, CD/blood/genetics MH - Antigens, Differentiation, Myelomonocytic/blood/genetics MH - Antiviral Agents/therapeutic use MH - Biomarkers/blood/cerebrospinal fluid MH - Chemokine CCL2/cerebrospinal fluid/genetics MH - Chemokine CXCL10/blood/genetics MH - *Cognition MH - Cognitive Dysfunction/cerebrospinal fluid/complications/*diagnosis/drug therapy MH - DNA, Mitochondrial/*cerebrospinal fluid MH - Disease Progression MH - Female MH - Gene Expression MH - HIV/drug effects/growth & development/pathogenicity MH - HIV Infections/cerebrospinal fluid/complications/*diagnosis/drug therapy MH - Humans MH - Interleukin-8/blood/genetics MH - Lipopolysaccharide Receptors/blood/genetics MH - Male MH - Middle Aged MH - Neuropsychological Tests MH - RNA, Viral/*blood MH - Receptors, Cell Surface/blood/genetics MH - Retrospective Studies MH - Tumor Necrosis Factor-alpha/blood/genetics PMC - PMC5538255 MID - NIHMS885927 OTO - NOTNLM OT - Inflammation OT - Neurocognitive performance OT - Neurodegeneration OT - ddPCR OT - mtDNA COIS- Competing Interests JPS, MFO, SRV, TRCD, SPW, SG and SRM declare that there is no competing interest. EDAT- 2016/12/07 06:00 MHDA- 2018/02/07 06:00 PMCR- 2018/04/01 CRDT- 2016/12/07 06:00 PHST- 2016/06/20 00:00 [received] PHST- 2016/11/01 00:00 [accepted] PHST- 2016/10/11 00:00 [revised] PHST- 2016/12/07 06:00 [pubmed] PHST- 2018/02/07 06:00 [medline] PHST- 2016/12/07 06:00 [entrez] PHST- 2018/04/01 00:00 [pmc-release] AID - 10.1007/s13365-016-0497-5 [pii] AID - 10.1007/s13365-016-0497-5 [doi] PST - ppublish SO - J Neurovirol. 2017 Apr;23(2):283-289. doi: 10.1007/s13365-016-0497-5. Epub 2016 Dec 5.