Immediate initiation of cART is associated with lower levels of cerebrospinal fluid YKL-40, a marker of microglial activation, in HIV-1 infection

Abstract

Objective To characterize cerebrospinal fluid (CSF) YKL-40, a unique biomarker that reflects activation of microglial cells, in acute (AHI) and chronic HIV-1 infection (CHI) and to determine the effect of treatment initiation on levels of this marker. Design Cross-sectional study of two groups of HIV-infected participants at baseline and follow-up timepoints. Methods AHI (n=33) and CHI (n=34) participants underwent CSF and blood sampling before treatment initiation with combination antiretroviral therapy (cART) and at follow up on cART in a subset of these individuals (6 months in AHI participants [n=24], 1 year in CHI participants [n=10]). Measured parameters were analyzed at each timepoint. Analyses employed Mann-Whitney tests and Spearman correlations. Results Baseline median YKL-40 was higher in CHI than AHI (96844 versus 80754 ng/L; p=0.011). Elevations in the CHI group relative to the AHI group persisted at follow-up despite treatment (87414 versus 66130 ng/L; p=0.003). In untreated CHI, YKL-40 correlated with neopterin (r=0.51, p=0.0025), chemokine (CXC-motif) ligand-10 (r=0.44, p=0.011), and neurofilament light chain (r=0.56, p=0.0008) in CSF. Conclusions This study is the first to describe the dynamics of CSF YKL-40 in two groups of HIV-infected individuals before and after cART and demonstrates the value of this marker in understanding HIV neuropathogenesis. The results suggest the utility of further exploring the prognostic value of YKL-40, particularly in individuals with early HIV infection or those initiating treatment during CHI.

High Number of Activated CD8+ T Cells Targeting HIV Antigens Are Present in Cerebrospinal Fluid in Acute HIV Infection

“…31 We found positive correlations with the frequency of activated CD8+ T cells in the CSF to early biomarkers of immune activation in the CNS (CSF neopterin, CSF IP-10, and CSF CD163) as well as CSF viral load at peak viremia in acute infection. These early markers of CNS inflammation did not correlate with activated CD8+ T cells in chronically-infected participants, where levels of NFL (biomarker of neuroaxonal injury) 32 and YKL-40 (CSF inflammatory marker) 33,34 correlated with the frequency of activated CD8+ T cells in the CSF. These results depict a very distinct immune response and inflammatory environment between acute and chronic infection and suggest that activated CD8+ T cells are recruited early in acute HIV infection responding to early neuroinflammatory markers in the CNS and might play a beneficial role in preventing neuronal damage if viral replication is halted at that stage by cART by killing HIV infected cells.…”

Molecular biomarkers of Alzheimer's disease: progress and prospects

“…Another glial marker, the C-C chemokine receptor 2, is expressed on monocytes, and one of its ligands, C-C chemokine ligand 2 (CCL2), which can be produced by microglia, is also present in increased concentrations in the CSF of AD patients ( Corrêa et al, 2011 ; Galimberti et al, 2006a , b ). Most studies suggest that these increases in glial proteins in AD are modest, with concentration ranges overlapping extensively between cases and controls, particularly when compared with the more prominent changes seen in ‘traditional’ neuroinflammatory conditions, such as multiple sclerosis ( Öhrfelt et al, 2016 ) or human immunodeficiency virus (HIV)-associated neurocognitive dysfunction ( Peluso et al, 2017 ). It should also be noted that all of the above-mentioned proteins, except TREM2, can also be released from activated astrocytes.…”

From Cerebrospinal Fluid to Blood: The Third Wave of Fluid Biomarkers for Alzheimer’s Disease

“…Another microglial marker, the C-C chemokine receptor 2, is expressed on monocytes and one of its ligands, C-C chemokine ligand 2 (CCL2), that can be produced by microglia, is present at increased concentration in AD CSF [67][68][69]. Most studies suggest that these increases are modest with large overlaps between cases and controls, if compared to the more prominent changes seen in traditional neuroinflammatory conditions, such as multiple sclerosis [70] or HIV-associated neurocognitive dysfunction [71]. When measured in plasma or serum, the concentrations of most of the microglia-related proteins mentioned above are higher than in CSF and probably reflect release from monocytes and macrophages in peripheral blood rather than CNS-related changes.…”