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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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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.
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Fig2: 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.

Mentions: Despite a higher CSF-to-plasma neopterin ratio in the high group (Figure 2A, P <0.001), the two groups did not differ in the CSF-to-plasma HIV RNA ratio (Figure 2B, P = 0.37) or the CSF-to-plasma albumin ratio (Figure 2C, P = 0.06). The neopterin-to-HIV RNA ratio was higher in the high group in CSF (P <0.001) but not in plasma (P = 0.10).Figure 2


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)

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

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

Fig2: 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.
Mentions: Despite a higher CSF-to-plasma neopterin ratio in the high group (Figure 2A, P <0.001), the two groups did not differ in the CSF-to-plasma HIV RNA ratio (Figure 2B, P = 0.37) or the CSF-to-plasma albumin ratio (Figure 2C, P = 0.06). The neopterin-to-HIV RNA ratio was higher in the high group in CSF (P <0.001) but not in plasma (P = 0.10).Figure 2

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