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Mitochondrial DNA Copy Number and
Neurocognitive Impairment in HIV-Infected
Persons....."mtDNA associated with worse cognitive outcomes".....both HIV & ART duration associated with mtDNA damage
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....."mtDNA associated with worse cognitive outcomes".....[from Jules: as you know from the early days of HIV where a lot of mtDNA research was conducted that both HIV & ART were found to be associated with mtDNA damage...here in this new study they found"].....both HIV viral load & ART are associated with mtDNA dysfunction..Higher PBMC mtDNA content was associated with worse neurocognitive performance in HIV+ adults.....Lower PBMC mtDNA copy number per cell was associated with lower platelet count (p=3e-7), older age (p=0.002) and longer ART duration (p=0.0008)"
Reported by Jules Levin
CROI 2015 Feb 22-24 Boston
David Samuels1; Asha R. Kallianpur2; Yan Guo3; Todd T. Brown4;
Sanjay R. Mehta5; Ron Ellis5; Scott R. Letendre5; Todd Hulgan3;
for the CHARTER study group
1Vanderbilt Univ Sch of Med, Nashville, TN, USA; 2Cleveland Clinic/
Lerner Rsr Inst, Cleveland, OH, USA; 3Vanderbilt Univ, Nashville,
TN, USA; 4Johns Hopkins Univ, Baltimore, MD, USA; 5Univ of
California San Diego, San Diego, CA, USA
Abstract
Mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells (PBMC) declines with age and has been associated with neurocognitive function in non-HIV-infected persons. Low mtDNA copy number may indicate disordered mtDNA replication and high copy number may indicate a cellular response to mitochondrial dysfunction. Extracellular (or "free") mtDNA is a TLR-9 ligand affecting the innate immune response. We tested relationships between both PBMC cellular mtDNA content and cerebrospinal fluid (CSF) cell-free mtDNA levels and neurocognitive impairment in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study.
PBMC mtDNA content was measured in 1011 CHARTER participants. The effect of PBMC mtDNA content on global deficit score (GDS), GDS impairment (GDS≥0.5), and HIV-Associated Neurocognitive Disorder (HAND) were tested by logistic regression, adjusting for platelet count, age, gender, genetic ancestry, comorbidity (incidental or contributing to neurocognitive impairment), nadir CD4 and HIV RNA in plasma. CSF free mtDNA was assessed by droplet digital PCR in a subset of 335 participants. 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), HIV viral load (VL), and GDS were evaluated.
Lower PBMC mtDNA copy number per cell was associated with lower platelet count (p=3e-7), older age (p=0.002) and longer ART duration (p=0.0008). PBMC mtDNA content was associated with GDS (p=0.02), GDS impairment (p=0.0003) and HAND (p=0.009). CSF free mtDNA levels were positively associated with CSF CXCL10 (p<0.001) and TNF-a (p<0.05). After adjusting for CSF WBC and VL, free mtDNA levels were associated with CSF inflammation- and iron-related biomarkers TF (p<0.05) and CP (p<0.05). With correction for ART, free mtDNA was associated with CSF VEGF (<0.05) and IL-6 (p=0.05). Unlike PBMC mtDNA, CSF free mtDNA was not associated with age or NCI.
Higher PBMC mtDNA content was associated with worse neurocognitive performance in HIV+ adults, although PBMC mtDNA content was lower with older age. Higher mtDNA content can be caused by increased replication in response to mitochondrial dysfunction, indicating a connection between neurocognitive impairment and a systemic decrease of mitochondrial function observable in PBMCs. Associations with CSF biomarkers indicate that CSF free mtDNA may mediate neuroinflammation during HIV infection.
WEBCAST:http://www.croiwebcasts.org/console/player/29723?mediaType=audio&
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