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. 2014 Dec 3;11:199.
doi: 10.1186/s12974-014-0199-y.

Progressive Increase in Central Nervous System Immune Activation in Untreated Primary HIV-1 Infection

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Free PMC article

Progressive Increase in Central Nervous System Immune Activation in Untreated Primary HIV-1 Infection

Joome Suh et al. J Neuroinflammation. .
Free PMC article

Abstract

Background: Central nervous system (CNS) inflammation is a mediator of brain injury in HIV infection. To study the natural course of CNS inflammation in the early phase of infection, we analyzed longitudinal levels of soluble and cellular markers of inflammation in cerebrospinal fluid (CSF) and blood, beginning with primary HIV-1 infection (PHI).

Methods: Antiretroviral-naïve subjects identified as having PHI (less than one year since HIV transmission) participated in phlebotomy and lumbar puncture at baseline and at variable intervals thereafter. Mixed-effects models were used to analyze longitudinal levels of CSF neopterin and percentages of activated cluster of differentiation (CD)4+ and CD8+ T-cells (co-expressing CD38 and human leukocyte antigen-D-related (HLA-DR)) in blood and CSF.

Results: A total of 81 subjects were enrolled at an average of 100 days after HIV transmission and had an average follow-up period of 321 days, with the number of visits ranging from one to 13. At baseline, the majority of subjects had CSF neopterin concentrations above the upper limit of normal. The baseline concentration was associated with the longitudinal trajectory of CSF neopterin. In subjects with baseline levels of less than 21 nmol/L, a cutoff value obtained from a mixed-effects model, CSF neopterin increased by 2.9% per 10 weeks (n = 33; P <0.001), whereas it decreased by 6.7% in subjects with baseline levels of more than 21 nmol/L (n = 11; P = 0.001). In a subset with available flow cytometry data (n = 42), the percentages of activated CD4+ and CD8+ T-cells in CSF increased by 0.8 (P <0.001) and 0.73 (P = 0.02) per 10 weeks, respectively.

Conclusions: Neopterin levels and the percentages of activated CD4+ and CD8+ T-cells in CSF progressively increase in most subjects without treatment during early HIV-1 infection, suggesting an accrual of intrathecal inflammation, a major contributor to neuropathology in HIV infection.

Figures

Figure 1
Figure 1
Trajectories of cerebrospinal fluid (CSF) neopterin in early HIV-1 infection. Thin lines represent the trajectories of individual subjects and bold lines represent the average slopes of high (red) and low (blue) groups (see text).
Figure 2
Figure 2
Cerebrospinal fluid-to-plasma ratios of baseline parameters in low and high groups. CSF, cerebrospinal fluid. A) CSF-to-plasma ratio of neopterin. B) CSF-to-plasma ratio of HIV RNA. C) CSF-to-plasma ratio of albumin.
Figure 3
Figure 3
Trajectories of percentages of activated T-cells in blood and CSF in early HIV-1 infection. Thin lines represent the trajectories of individual subjects and bold lines represent average slopes obtained from mixed-effects models. A) Percentage of CD4+ CD38+ HLA-DR+ cells in blood. B) Percentage of CD8+ CD38+ HLA-DR+ cells in blood. No significant trend was observed. C) Percentage of CD4+ CD38+ HLA-DR+ cells in CSF. D) Percentage of CD8+ CD38+ HLA-DR+ cells in CSF. CD, cluster of differentiation; CSF, cerebrospinal fluid; HLA-DR, human leukocyte antigen-D-related.

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