title: Cell-free mitochondrial DNA in CSF is associated with early viral rebound, inflammation, and severity of neurocognitive deficits in HIV infection.
abstract: Cell-free mitochondiral DNA (mtDNA) is an immunogenic molecule associated with many inflammatory conditions. We evaluated the relationship between cell-free mtDNA in cerebrospinal fluid (CSF) and neurocognitive performance and inflammation during HIV infection. In a cross-sectional analysis, we evaluated the association of mtDNA levels with clinical assessments, inflammatory markers, and neurocognitive performance in 28 HIV-infected individuals. In CSF, we measured mtDNA levels by droplet digital PCR, and soluble CD14 and CD163, neurofilament light, and neopterin by ELISA. In blood and CSF, we measured soluble IP-10, MCP-1, TNF-α, and IL-6 by ELISA, and intracellular expression of IL-2, IFN-γ, and TNF-α in CD4(+) and CD8(+) T cells by flow cytometry. We also evaluated the relationship between CSF pleocytosis and mtDNA longitudinally in another set of five individuals participating in an antiretroviral treatment (ART) interruption study. Cell-free CSF mtDNA levels strongly correlated with neurocognitive performance among individuals with neurocognitive impairment (NCI) (r = 0.77, p = 0.001). CSF mtDNA also correlated with levels of IP-10 in CSF (r = 0.70, p = 0.007) and MCP-1 in blood plasma (r = 0.66, p = 0.01) in individuals with NCI. There were no significant associations between inflammatory markers and mtDNA in subjects without NCI, and levels of mtDNA did not differ between subjects with and without NCI. MtDNA levels preceded pleocytosis and HIV RNA following ART interruption. Cell-free mtDNA in CSF was strongly associated with the severity of neurocognitive dysfunction and inflammation only in individuals with NCI. Our findings suggest that within a subset of subjects cell-free CSF mtDNA is associated with inflammation and degree of NCI.
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.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: Rachel D
authors.initials: RD
authors.lastname: Schrier
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: 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.
authors.forename: Susanna R
authors.initials: SR
authors.lastname: Var
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.
authors.forename: Tyler R C
authors.initials: TR
authors.lastname: Day
authors.affiliation: University of Alberta, Edmonton, AB, Canada.
authors.forename: Miguel
authors.initials: M
authors.lastname: Ramirez-Gaona
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Suben
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Murrell
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Massanella
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Cherner
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: Davey M
authors.initials: DM
authors.lastname: Smith
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Ellis
authors.affiliation: University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Letendre
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 / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D054357:Chemokine CXCL10 / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000150:complications / Q000276:immunology / Q000473:pathology; D003430:Cross-Sectional Studies; D004272:DNA, Mitochondrial / Q000134:cerebrospinal fluid*; D056344:Executive Function; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000134:cerebrospinal fluid* / Q000150:complications / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D015850:Interleukin-6 / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D007858:Learning; D018950:Lipopolysaccharide Receptors / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D008297:Male; D008568:Memory; D008875:Middle Aged; D019798:Neopterin / Q000134:cerebrospinal fluid / Q000276:immunology; D016900:Neurofilament Proteins / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D009483:Neuropsychological Tests; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha / Q000134:cerebrospinal fluid / Q000235:genetics / Q000276:immunology; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C111835:CCL2 protein, human; D000098902:CD163 Antigen; C114753:CXCL10 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D004272:DNA, Mitochondrial; C508600:IL6 protein, human; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D016900:Neurofilament Proteins; D011956:Receptors, Cell Surface; D014409:Tumor Necrosis Factor-alpha; C044882:neurofilament protein L; D019798:Neopterin
keywords: Droplet digital PCR; HAND; Inflammation; Mitochondrial DNA; Pleocytosis