Cerebrospinal fluid cell-free mitochondrial DNA is associated with HIV replication, iron transport, and mild HIV-associated neurocognitive impairment
Year: 2017
Type: article
Abstract: BACKGROUND: Mitochondria are abundant organelles critical for energy metabolism and brain function. Mitochondrial DNA (mtDNA), released during cellular injury and as part of the innate immune response to viral pathogens, contains CpG motifs that act as TLR-9 ligands. We investigated relationships between cerebrospinal fluid (CSF) cell-free mtDNA levels and HIV viral load (VL), biomarkers of inflammation and iron transport, and neurocognitive (NC) function in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort. METHODS: We quantified cell-free mtDNA in CSF by droplet digital PCR in 332 CHARTER participants who underwent comprehensive neuropsychiatric evaluation. NC performance was assessed using the global deficit score (GDS) as either a continuous or a binary measure (GDS ≥ 0.5, impaired vs. GDS < 0.5, unimpaired). CSF, clinical, and biomarker data from the earliest available time point were analyzed. Cell-free mtDNA associations with CSF inflammation and iron-related biomarkers [CXCL10, IL-6, IL-8, TNF-a, transferrin (TF), ceruloplasmin (CP), and vascular endothelial growth factor (VEGF)], VL, and GDS were evaluated by multivariable regression. RESULTS: CSF cell-free mtDNA levels were significantly lower in participants with undetectable (vs. detectable) VL in either plasma (p < 0.001) or CSF (p < 0.001) and in those on antiretroviral therapy (ART; p < 0.001). Participants on ART with undetectable VL in both CSF and plasma had lower mtDNA levels than those with detectable VL in both compartments (p = 0.001). Higher mtDNA levels were observed in participants in the highest vs. lowest tertile (T3 vs. T1) of CSF CXCL10 (T3 vs. T1, p < 0.001) and TNF-a (T3 vs. T1, p < 0.05) in unadjusted analyses. MtDNA levels also correlated with CSF leukocyte count. After adjusting for CSF leukocyte count and VL, mtDNA levels were also associated with other inflammation- and iron-related biomarkers in CSF, including TF (T3 vs. T1, p < 0.05) and CP (T3 vs. T1, p < 0.05). With additional correction for ART use, mtDNA was also negatively associated with CSF VEGF (p < 0.05) and IL-6 (p = 0.05). We observed no associations of CSF mtDNA levels with age or GDS-defined NC impairment. CONCLUSIONS: CSF cell-free mtDNA levels were associated with HIV RNA and ART status, as well as with biomarkers of iron transport and VEGF, a growth factor with known effects on mitochondrial integrity and autophagy. CSF mtDNA may be a biomarker of iron dysregulation and/or neuroinflammation during HIV infection.
Source: Journal of Neuroinflammation
Authors: Sanjay R. Mehta, Josué Pérez-Santiago, Todd Hulgan, Tyler R. C. Day, Jill Barnholtz-Sloan, Haley Gittleman, Scott Letendre, Ronald Ellis, Robert Heaton, Stephanie Patton, Jesse D. Suben, Donald Franklin, Debralee Rosario, David B. Clifford, Ann C. Collier, Christina M. Marra, Benjamin B. Gelman, Justin McArthur, Allen McCutchan, Susan Morgello, David Simpson, James Connor, Igor Grant, Asha Kallianpur
Institutions: University of California San Diego, Vanderbilt University, Washington University in St. Louis, Case Comprehensive Cancer Center, Case Western Reserve University, Pennsylvania State University, Penn State Milton S. Hershey Medical Center, University of Washington, The University of Texas Medical Branch at Galveston, Johns Hopkins University, Icahn School of Medicine at Mount Sinai, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,090
Funders: Alzheimer's Association, University of Washington, Johns Hopkins University, National Institutes of Health, University of California, San Diego, National Institute of Mental Health, National Institute of Nursing Research, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences, HIV Neurobehavioral Research Center, University of California, San Diego
Awards: G1047363770, G1286378763, G1551097431, WASHINGTON UNIVERSITY AIDS CLINICAL TRIALS UNIT, G1857077138, G1982323743, G2135258891, G2202404319, G25173860, Washington University Network of Excellence in Neuroscience Clinical Trials Site, G2910247735, CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER), G3350118538, THE EFFECTS OF AGE AND HIGHLY ACTIVE ANTIRETROVIRAL THERAPY ON BRAIN FUNCTION, G3813128133, G4152506234, G4797509974, G5209633835, Texas NeuroAIDS Research Center, G6105309749, G6391991693, Frailty and Brain Integrity in Older HIV-infected Individuals, Midcareer Investigator Award in Patient-Oriented NeuroAIDS Research, G8679799747, G9000005743, G9000012953, G9000065455, G9000074518, G9000115080, G9000133689, G9000166604, G9000211129, G9000228402, G9000243423, San Diego Center for AIDS Research (SD CFAR), HIV Neurobehavioral Research Center, G936311976
OpenAlex ID: W2603786624