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CCR2 on Peripheral Blood CD14+CD16+ Monocytes Correlates with Neuronal Damage, HIV-Associated Neurocognitive Disorders, and Peripheral HIV DNA: reseeding of CNS reservoirs?

Abstract

HIV-associated neurocognitive disorders (HAND) occur in ~50% of HIV infected individuals despite combined antiretroviral therapy. Transmigration into the CNS of CD14+CD16+ monocytes, particularly those that are HIV infected and express increased surface chemokine receptor CCR2, contributes to neuroinflammation and HAND. To examine whether in HIV infected individuals CCR2 on CD14+CD16+ monocytes serves as a potential peripheral blood biomarker of HAND, we examined a cohort of 45 HIV infected people. We correlated CCR2 on CD14+CD16+ monocytes with cognitive status, proton magnetic resonance spectroscopy (1H-MRS) measured neurometabolite levels, and peripheral blood mononuclear cell (PBMC) HIV DNA copies. We determined that CCR2 was increased specifically on CD14+CD16+ monocytes from people with HAND (median [interquartile range (IQR)]) (63.3 [51.6, 79.0]), compared to those who were not cognitively impaired (38.8 [26.7, 56.4]) or those with neuropsychological impairment due to causes other than HIV (39.8 [30.2, 46.5]). CCR2 was associated with neuronal damage, based on the inverse correlation of CCR2 on CD14+CD16+ monocytes with total N-Acetyl Aspartate (tNAA)/total Creatine (tCr) (r2 = 0.348, p = 0.01) and Glutamine-Glutamate (Glx)/tCr (r2 = 0.356, p = 0.01) in the right and left caudate nucleus, respectively. CCR2 on CD14+CD16+ monocytes also correlated with PBMC HIV DNA copies (ρ = 0.618, p = 0.02) that has previously been associated with HAND. These findings suggest that CCR2 on CD14+CD16+ monocytes may be a peripheral blood biomarker of HAND, indicative of increased HIV infected CD14+CD16+ monocyte entry into the CNS that possibly increases the macrophage viral reservoir and contributes to HAND.

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Acknowledgements

The authors thank MHBB staff and patients who generously contributed their time to the study. This study was funded by National Institutes of Health U24MH100931 (MHBB) (S.M.), R01MH075679 (J.W.B.), R21MH102113-01A1 (J.W.B), R01MH090958 (J.W.B.), R01MH112391 (T.M.C., J.W.B.), R01NS077869 (J.E.C), R01AI127142 (J.E.C.), P30AI124414 (ERC CFAR) (M.V., R.L-R., T.M.C., J.W.B.), Mount Sinai Institute for NeuroAIDS Disparities (R25 MH080663) (R.L-R.), MSTP Training Grant at Albert Einstein College of Medicine (5T32GM007288) (R.L-R.), TL1TR001072 (Einstein-Montefiore CTSA) (M.V.), pilot research grant Icahn School of Medicine Brain Imaging Center (S.M.), National MS Society RG 5120A3/1 (M.I.), and eCLIPSE fellowship (M.V.), Burroughs Wellcome Foundation Grant program “Unifying Population and Laboratory Science”.

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Correspondence to Susan Morgello or Joan W. Berman.

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Veenstra, M., Byrd, D.A., Inglese, M. et al. CCR2 on Peripheral Blood CD14+CD16+ Monocytes Correlates with Neuronal Damage, HIV-Associated Neurocognitive Disorders, and Peripheral HIV DNA: reseeding of CNS reservoirs?. J Neuroimmune Pharmacol 14, 120–133 (2019). https://doi.org/10.1007/s11481-018-9792-7

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Keywords

  • HAND
  • CD14+CD16+ Monocytes
  • CCR2
  • MRI/MRS
  • HIV
  • ddPCR