CD8+ lymphocyte depletion without SIV infection does not produce metabolic changes or pathological abnormalities in the rhesus macaque brain

Abstract

Background: Simian immunodeficiency virus (SIV) infection and persistent CD8(+) lymphocyte depletion rapidly leads to encephalitis and neuronal injury. The objective of this study is to confirm that CD8 depletion alone does not induce brain lesions in the absence of SIV infection.

Methods: Four rhesus macaques were monitored by proton magnetic resonance spectroscopy ((1) H-MRS) before and biweekly after anti-CD8 antibody treatment for 8 weeks and compared with four SIV-infected animals. Post-mortem immunohistochemistry was performed on these eight animals and compared with six uninfected, non-CD8-depleted controls.

Results: CD8-depleted animals showed stable metabolite levels and revealed no neuronal injury, astrogliosis or microglial activation in contrast to SIV-infected animals.

Conclusions: Alterations observed in MRS and lesions in this accelerated model of neuroAIDS result from unrestricted viral expansion in the setting of immunodeficiency rather than from CD8(+) lymphocyte depletion alone.

Figure 1

Representative 7 Tesla MR spectrum acquired from the frontal cortex an animal prior to CD8 depletion. ¹H MR spectra are characterized by resonances primarily arising from N-acetylaspartate and N-acetylaspartylglutamate (collectively referred to as NAA), choline-containing compounds (referred to as Cho), myo-Inositol (MI), creatine-containing compounds (referred to as Cr) and the glutamate and glutamine concentrations (so-called Glx).

Figure 2

Figure 2 (a). Changes in Glx/Cr, NAA/Cr, MI/Cr, and Cho/Cr in the white matter semiovale before and after CD8+ lymphocyte depletion in one representative animal over time. None of the metabolite ratios showed any change due to the anti-CD8 treatment. Figure 2 (b). Mean NAA/Cr ratios of the four CD8-depleted animals in the white matter (WM), frontal cortex (FC), and basal ganglia (BG) as a function of time post-CD8 depletion. No significant changes in any of the brain regions over time were found. The error bars represent standard error of the mean (SEM).

Figure 3

Quantitative image analysis of immunohistochemistry reveals no difference between CD8-depleted, uninfected animals (CD8-) and non-CD8-depleted, uninfected controls (Control) in (a) SYN, (b) MAP2, (c) GFAP and (d) IBA-1; however, there are significant differences in SYN, GFAP and IBA-1 between SIV-infected, CD8-depleted animals (SIV+/CD8-) and these two control cohorts. Horizontal bars within boxes represent mean values; height of each box corresponds to standard error of the mean.