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Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection.

Suh J, Sinclair E, Peterson J, Lee E, Kyriakides TC, Li FY, Hagberg L, Fuchs D, Price RW, Gisslen M, Spudich S - J Neuroinflammation (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Yale School of Medicine, 367 Cedar Street, New Haven, CT 06510, USA. joome.suh@yale.edu.

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.

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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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Fig3: 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.

Mentions: Mixed-model analyses of subjects with available flow cytometry data (n = 42) showed an increasing trend in the percentage of activated CD4+ cells in blood at a rate of 0.23 per 10 weeks (P = 0.05, Figure 3A). A significant trend for activated CD8+ cells in blood was not found (P = 0.54, Figure 3B). In CSF, the percentage of activated CD4+ cells increased at a rate of 0.63 per 10 weeks (P = 0.04). We noted an outlier value that had a sharp increase from 8 to 54% from day 26 to 51 post-transmission; re-analysis excluding this outlier yielded a rate of 0.8 per 10 weeks (P <0.001, Figure 3C). The percentage of activated CD8+ cells in CSF increased at a rate of 0.73 per 10 weeks (P = 0.02, Figure 3D).Figure 3


Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection.

Suh J, Sinclair E, Peterson J, Lee E, Kyriakides TC, Li FY, Hagberg L, Fuchs D, Price RW, Gisslen M, Spudich S - J Neuroinflammation (2014)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4263211&req=5

Fig3: 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.
Mentions: Mixed-model analyses of subjects with available flow cytometry data (n = 42) showed an increasing trend in the percentage of activated CD4+ cells in blood at a rate of 0.23 per 10 weeks (P = 0.05, Figure 3A). A significant trend for activated CD8+ cells in blood was not found (P = 0.54, Figure 3B). In CSF, the percentage of activated CD4+ cells increased at a rate of 0.63 per 10 weeks (P = 0.04). We noted an outlier value that had a sharp increase from 8 to 54% from day 26 to 51 post-transmission; re-analysis excluding this outlier yielded a rate of 0.8 per 10 weeks (P <0.001, Figure 3C). The percentage of activated CD8+ cells in CSF increased at a rate of 0.73 per 10 weeks (P = 0.02, Figure 3D).Figure 3

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Yale School of Medicine, 367 Cedar Street, New Haven, CT 06510, USA. joome.suh@yale.edu.

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.

Show MeSH
Related in: MedlinePlus