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. 2016 Aug;32(8):791-800.
doi: 10.1089/AID.2015.0313. Epub 2016 May 2.

Immune Activation and HIV-Specific CD8(+) T Cells in Cerebrospinal Fluid of HIV Controllers and Noncontrollers

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Free PMC article

Immune Activation and HIV-Specific CD8(+) T Cells in Cerebrospinal Fluid of HIV Controllers and Noncontrollers

Anupama Ganesh et al. AIDS Res Hum Retroviruses. .
Free PMC article

Abstract

The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine whether HIV-specific CD8(+) T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL <40 copies/ml) and two viremic controllers (VC, VL 40-2,000 copies/ml). All controllers had CSF VL <40 copies/ml. Three comparison groups were also sampled: six HIV noncontrollers (NC, VL >10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL <40 copies/ml); and nine HIV-negative controls. CD4(+) and CD8(+) T cells in CSF and blood were analyzed by flow cytometry to assess expression of CCR5, activation markers CD38 and HLA-DR, and memory/effector markers CD45RA and CCR7. HIV-specific CD8(+) T cells were quantified by major histocompatibility complex class I multimer staining. HIV-specific CD8(+) T cells were detected ex vivo at similar frequencies in CSF of HC and noncontrollers; the highest frequencies were in individuals with CD4 counts below 500 cells/μl. The majority of HIV-specific CD8(+) T cells in CSF were effector memory cells expressing CCR5. Detection of these cells in CSF suggests active surveillance of the CNS compartment by HIV-specific T cells, including in individuals with long-term control of HIV infection in the absence of therapy.

Figures

<b>FIG. 1.</b>
FIG. 1.
MHC class I multimer staining and multicolor phenotyping. (A) Shows flow cytometry bivariate contour plots for whole blood (top two rows) and CSF (bottom two rows). At the far left, MHC class I multimer staining (y-axis) is plotted versus CD8 (x-axis). The heavy black rectangle indicates cells staining positive for CD8, which are further delineated in the bivariate plots labeled “All CD8+” at right. The heavy red square in the upper right quadrant indicates CD8+ T cells stained with MHC class I multimer, which are further delineated in the bivariate plots labeled “Tetramer+” at right. Three additional surface staining combinations are shown: from left to right, CCR7 (y-axis) versus CCR5 (x-axis); CCR7 (y-axis) versus CD45RA (x-axis); and HLA-DR (y-axis) versus CD38 (x-axis). Numbers in each quadrant indicate the percentages of cells in that quadrant. All data in (A) were from an HIV noncontroller, subject number 7193. (B) Shows the percentage of CD8+ T cells that bound MHC class I multimers in HIV controllers (blue shapes) or noncontrollers (red shapes). Values for CSF are indicated by triangles; values for blood are indicated by squares. Each subject corresponds to a single line connecting blood and CSF values. For one subject, noncontroller 9016, PBMC were stained instead of whole blood (0.544%). Asterisks indicate samples from subjects specifically discussed in the text, as follows: left side, shown in blue: *HIV controller 7190; **HIV controller 7109; right side, shown in red: *HIV noncontroller 7193; **HIV noncontroller 4141. CSF, cerebrospinal fluid; MHC, major histocompatibility complex; PBMC, peripheral blood mononuclear cells.
<b>FIG. 2.</b>
FIG. 2.
(A) Shows the breakdown of CD8+ T cells in whole blood and CSF that had a central memory, effector memory, or “TEMRA” (terminally differentiated, RA expressing) phenotype. HC, HIV controllers (blue shapes); NC, noncontrollers (red shapes); Tx, subjects on ART with VL <50 (green shapes); Neg, HIV-negative controls (black shapes). Lines and asterisks above the graphs indicate p values for statistically significant differences between groups (*p < .05; **p < .01). (B) Summarizes the percentages of HIV-specific CD8+ T cells (i.e., binding MHC class I multimers) that were effector memory cells. ART, antiretroviral therapy; VL, viral load.
<b>FIG. 3.</b>
FIG. 3.
(A) The top row shows the percentage of all CD4+ T cells (left) or all CD8+ T cells (right) in blood or CSF that were positive for CCR5. Second row: the graph shows the percentages of HIV-specific CD8+ T cells (i.e., binding MHC class I multimers) that were positive for CCR5 in blood or CSF. HC, HIV controllers (blue shapes); NC, noncontrollers (red shapes); Tx, subjects on ART with VL <50 (green shapes); Neg, HIV-negative controls (black shapes). Lines and asterisks above the graphs indicate p values for statistically significant differences between groups (*p < .05; **p < .01; ***p < 0.001). (B) Shows the percentage of all CD4+ T cells (left) or all CD8+ T cells (right) in blood or CSF that coexpressed the activation markers HLA-DR and CD38. The third panel shows the percentages of HIV-specific CD8+ T cells (i.e., binding MHC class I multimers) that were positive for both HLA-DR and CD38 in blood or CSF. Lines and asterisks above the graphs indicate p values for statistically significant differences between groups (*p < .05).
<b>FIG. 4.</b>
FIG. 4.
Neopterin. The graph shows levels of neopterin (nM) measured in CSF (triangles) and plasma (squares) obtained from participants in each group. HC, HIV controllers (blue shapes); NC, noncontrollers (red shapes); Tx, subjects on ART with VL <50 (green shapes); Neg, HIV-negative controls (black shapes). Lines and asterisks above the graphs indicate p values for statistically significant differences between groups (*p < .05; **p < .01; ***p < .001).

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