Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2014 Dec 26;9(12):e116081.
doi: 10.1371/journal.pone.0116081. eCollection 2014.

Cerebrospinal Fluid (CSF) Neuronal Biomarkers Across the Spectrum of HIV Infection: Hierarchy of Injury and Detection

Affiliations
Free PMC article

Cerebrospinal Fluid (CSF) Neuronal Biomarkers Across the Spectrum of HIV Infection: Hierarchy of Injury and Detection

Julia Peterson et al. PLoS One. .
Free PMC article

Abstract

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200-349, 50-199, and <50 cells/µL; HAD; treatment-induced viral suppression; and 'elite' controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1-42, 1-40 and 1-38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50-199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management.

Conflict of interest statement

Competing Interests: The authors have no competing interests that could be construed as influencing the contents of this paper. However the authors list the following general potential conflicts of interest: RWP has been a consultant to Merck and Co and has received an honorarium and travel support from Abbott Laboratories/AbbVie for meeting presentations. MG has received research grants from Abbott, Baxter, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche and Tibotec, and he has received honoraria as a speaker and/or advisor from Abbott/Abbvie, Bioinvent, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Merck, Pfizer, Roche and Tibotec/Janssen. SS has received an honorarium and travel support from AbbVie, Inc. for a meeting presentation. HZ reports no conflicts. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Concentrations of 6 CSF neuronal biomarkers in the 9 subject groups.
Boxes in all panels depict median and IQR, whiskers show 10–90 percentiles and ‘+’ designate the means. Dotted horizontal lines show the limits of laboratory norms for the older age groups where available (upper limit of normal for NFL, t-tau and p-tau and lower limit of normal for Aβ42). Statistical comparisons of groups are given in Table 3. The biomarker concentrations are displayed in a log10 ng/L, over a 3 times log10 range, but at a higher scale range for NFL. Measured markers are listed in the title of each panel and findings described in the text. Some of the CSF NFL results included here have been previously reported in a different context , , , including within a larger data set characterizing CSF in relation to age ; here, the number of subject groups is expanded and we emphasize the comparison of NFL with the other neuronal biomarkers which have not been previously reported.
Figure 2
Figure 2. Ratios of selected neuronal biomarkers.
The plots are similar in format to those of Fig. 1, but plot ratios (log10 differences) of selected neuronal biomarkers on log10 scales that differ in relation to the magnitude and ranges of the differences. A. Ratio of CSF p-tau to t-tau in the nine groups. Only the HAD group differed from any of the others in Dunn's multiple comparison test: compared to Rx suppressed and CD4 >350 (p<0.0001); to CD4 200–349 (p<0.01); and to CD4 50–199 (p<0.05). B. Ratio of CSF NFL to CSF sAPPβ. HAD group differed from HIV- and PHI (p<0.0001), from Rx suppressed, CD4+>350, CD4+200–349, CD4+50–199 (p<0.001); CD4<50 differed from HIV- (p<0.001) and from CD4+>350 (p<0.05). C. Ratio of CSF t-tau to sAPPβ. The HAD group differed from HIV-, Rx suppressed and PHI (p<0.0001), from CD4 200–349 (p<0.001), from CD4 >350 (p<0.01), from CD4 50–199 and from PHI (p<0.05); CD4<50 differed from PHI (p<0.05).
Figure 3
Figure 3. Concentrations of biomarkers in redefined NA subject and HAD groups.
The left 6 panels (A–F) show concentrations of six CSF neuronal biomarkers in the four redefined subject groups discussed in text using same log10 axes as Fig. 1. The right six panels show some of the main background variables with vertical axes defined for each panel. The size of each re-sorted group was: CD<200, N = 40; NFL-, N = 22; NFL+, N = 18; HAD, N = 12). The horizontal brackets show p values for significant group differences by Dunn's multiple comparison test after Kruskal-Wallis test: * = <0.05, ** = <0.01, *** = <0.001 and **** = <0.0001.
Figure 4
Figure 4. Progression to severe HIV-related CNS injury.
The figure outlines a simple diagram of transition from asymptomatic NFL- infection to either ‘quiet’ NFL+ injury or HAD. It emphasizes that both have CD4+ T-cell loss in common but then diverge for undefined reasons, possibly related to viral evolution of host inflammatory/immune activation characteristics. Further study is needed to understand the factors operating in this transition. It also has not been defined whether either of these two injury states can transition to the other.

Similar articles

See all similar articles

Cited by 44 articles

See all "Cited by" articles

References

    1. Davis LE, Hjelle BL, Miller VE, Palmer DL, Llewellyn AL, et al. (1992) Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology 42:1736–1739. - PubMed
    1. Spudich S, Gisslen M, Hagberg L, Lee E, Liegler T, et al. (2011) Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. The Journal of infectious diseases 204:753–760. - PMC - PubMed
    1. Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S, et al. (2012) Central nervous system viral invasion and inflammation during acute HIV infection. The Journal of infectious diseases 206:275–282. - PMC - PubMed
    1. Peluso MJ, Meyerhoff DJ, Price RW, Peterson J, Lee E, et al. (2013) Cerebrospinal Fluid and Neuroimaging Biomarker Abnormalities Suggest Early Neurological Injury in a Subset of Individuals During Primary HIV Infection. The Journal of infectious diseases 207:1703–1712. - PMC - PubMed
    1. Ellis RJ, Hsia K, Spector SA, Nelson JA, Heaton RK, et al. (1997) Cerebrospinal fluid human immunodeficiency virus type 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. HIV Neurobehavioral Research Center Group. Annals of neurology 42:679–688. - PubMed

Publication types

MeSH terms

Feedback