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Cell-free mitochondrial DNA in CSF is associated with early viral rebound, inflammation, and severity of neurocognitive deficits in HIV infection

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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.

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Acknowledgments

This work was supported by the Department of Veterans Affairs and grants from the National Institutes of Health: AI093163, AI100665, AI036214, AI007384, MH062512, MH081482, MH101012, DA026306, 1S10RR031646-01, PST5TP2, MH097673; the James B. Pendleton Charitable Trust; and the CNPq-Brazil [MFO]. Additionally, the authors would like to acknowledge the contribution of the research volunteers, the CFAR Genomics and Translational Virology Cores, and the HNRP. Particularly, we would like to thank Parris S. Jordan and Michael Potter for helping with the measurements of soluble inflammatory markers.

Conflict of interest

JPS, RC, MFO, SG, SRV, TRCD, MRG, JDS, BM, MM, MC, RJE, and SRM do not have any commercial or other associations that might pose a conflict of interest. DMS has received grant support from ViiV Pharmaceuticals and has served as consultant for Gen-Probe, Hologic, and Testing Talent Services. SLL has served as a consultant for GlaxoSmithKline and Merck & Co.

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Authors and Affiliations

  1. University of California San Diego, 9500 Gilman Drive MC 0679, La Jolla, CA, 92093-0679, USA

    Josué Pérez-Santiago, Rachel D. Schrier, Michelli F. de Oliveira, Sara Gianella, Susanna R. Var, Tyler R. C. Day, Jesse D. Suben, Ben Murrell, Marta Massanella, Mariana Cherner, Davey M. Smith, Ronald J. Ellis, Scott L. Letendre & Sanjay R. Mehta

  2. Veterans Administration San Diego Healthcare System, San Diego, CA, USA

    Davey M. Smith & Sanjay R. Mehta

  3. University of Alberta, Edmonton, AB, Canada

    Miguel Ramirez-Gaona

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  1. Josué Pérez-Santiago
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  2. Rachel D. Schrier
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Correspondence to Josué Pérez-Santiago.

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Pérez-Santiago, J., Schrier, R.D., de Oliveira, M.F. et al. Cell-free mitochondrial DNA in CSF is associated with early viral rebound, inflammation, and severity of neurocognitive deficits in HIV infection. J. Neurovirol. 22, 191–200 (2016). https://doi.org/10.1007/s13365-015-0384-5

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  • DOI: https://doi.org/10.1007/s13365-015-0384-5

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