Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

Stephanie M. Patton, Quan Wang, Todd Hulgan, James R. Connor, Peilin Jia, Zhongming Zhao, Scott L. Letendre, Ronald J. Ellis, William S. Bush, David C. Samuels, Donald R. Franklin, Harpreet Kaur, Jennifer Iudicello, Igor Grant, Asha R. Kallianpur

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Abstract

Background: HIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND. Methods: We quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (QAlb) measurements, QAlb and comorbidity severity were also included as covariates to account for variability in the blood-CSF-barrier. Results: Among 403 individuals (median age 43 years, 19% women, 56% non-Whites, median nadir CD4+ T cell count 180 cells/μL, 46% with undetectable plasma virus), men had 25% higher CSF transferrin (median 18.1 vs. 14.5 μg/mL), and 71% higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41% higher in self-reported Hispanics and 27% higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 μg/dL in Hispanics and Whites, respectively, vs. 3.7 μg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25% higher (p < 0.05), and transferrin 14% higher (p = 0.06), in Whites than Blacks. Transferrin and H-ferritin were 33 and 50% higher, respectively, in older (age > 50 years) than in younger persons (age ≤ 35 years; both p < 0.01), but these findings lost statistical significance in subset analyses that adjusted for QAlb and comorbidity. After these additional adjustments, associations were observed for CSF iron and transferrin with race/ethnicity as well as CSF VL, for transferrin with sex and ART, and for H-ferritin with plasma virus detectability and significant comorbidity (all p < 0.05). Conclusions: CSF iron biomarkers are associated with demographic factors, ART, and CSF VL in HIV+ adults. Future studies should investigate a role for CNS iron dysregulation, to which an altered blood-CSF barrier may contribute, in HAND.

Original languageEnglish (US)
Article number11
JournalFluids and Barriers of the CNS
Volume14
Issue number1
DOIs
StatePublished - Apr 21 2017

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Viral Load
Cerebrospinal Fluid
Iron
Biomarkers
Demography
HIV
Apoferritins
Transferrin
Therapeutics
Comorbidity
Viruses
Hispanic Americans
Social Adjustment
Spinal Puncture
CD4 Lymphocyte Count
Immunoassay
Serum Albumin
Observational Studies
Carrier Proteins
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience

Cite this

Patton, Stephanie M. ; Wang, Quan ; Hulgan, Todd ; Connor, James R. ; Jia, Peilin ; Zhao, Zhongming ; Letendre, Scott L. ; Ellis, Ronald J. ; Bush, William S. ; Samuels, David C. ; Franklin, Donald R. ; Kaur, Harpreet ; Iudicello, Jennifer ; Grant, Igor ; Kallianpur, Asha R. / Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults. In: Fluids and Barriers of the CNS. 2017 ; Vol. 14, No. 1.
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title = "Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults",
abstract = "Background: HIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND. Methods: We quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (QAlb) measurements, QAlb and comorbidity severity were also included as covariates to account for variability in the blood-CSF-barrier. Results: Among 403 individuals (median age 43 years, 19{\%} women, 56{\%} non-Whites, median nadir CD4+ T cell count 180 cells/μL, 46{\%} with undetectable plasma virus), men had 25{\%} higher CSF transferrin (median 18.1 vs. 14.5 μg/mL), and 71{\%} higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41{\%} higher in self-reported Hispanics and 27{\%} higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 μg/dL in Hispanics and Whites, respectively, vs. 3.7 μg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25{\%} higher (p < 0.05), and transferrin 14{\%} higher (p = 0.06), in Whites than Blacks. Transferrin and H-ferritin were 33 and 50{\%} higher, respectively, in older (age > 50 years) than in younger persons (age ≤ 35 years; both p < 0.01), but these findings lost statistical significance in subset analyses that adjusted for QAlb and comorbidity. After these additional adjustments, associations were observed for CSF iron and transferrin with race/ethnicity as well as CSF VL, for transferrin with sex and ART, and for H-ferritin with plasma virus detectability and significant comorbidity (all p < 0.05). Conclusions: CSF iron biomarkers are associated with demographic factors, ART, and CSF VL in HIV+ adults. Future studies should investigate a role for CNS iron dysregulation, to which an altered blood-CSF barrier may contribute, in HAND.",
author = "Patton, {Stephanie M.} and Quan Wang and Todd Hulgan and Connor, {James R.} and Peilin Jia and Zhongming Zhao and Letendre, {Scott L.} and Ellis, {Ronald J.} and Bush, {William S.} and Samuels, {David C.} and Franklin, {Donald R.} and Harpreet Kaur and Jennifer Iudicello and Igor Grant and Kallianpur, {Asha R.}",
year = "2017",
month = "4",
day = "21",
doi = "10.1186/s12987-017-0058-1",
language = "English (US)",
volume = "14",
journal = "Fluids and Barriers of the CNS",
issn = "2045-8118",
publisher = "BioMed Central",
number = "1",

}

Patton, SM, Wang, Q, Hulgan, T, Connor, JR, Jia, P, Zhao, Z, Letendre, SL, Ellis, RJ, Bush, WS, Samuels, DC, Franklin, DR, Kaur, H, Iudicello, J, Grant, I & Kallianpur, AR 2017, 'Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults', Fluids and Barriers of the CNS, vol. 14, no. 1, 11. https://doi.org/10.1186/s12987-017-0058-1

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults. / Patton, Stephanie M.; Wang, Quan; Hulgan, Todd; Connor, James R.; Jia, Peilin; Zhao, Zhongming; Letendre, Scott L.; Ellis, Ronald J.; Bush, William S.; Samuels, David C.; Franklin, Donald R.; Kaur, Harpreet; Iudicello, Jennifer; Grant, Igor; Kallianpur, Asha R.

In: Fluids and Barriers of the CNS, Vol. 14, No. 1, 11, 21.04.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults

AU - Patton, Stephanie M.

AU - Wang, Quan

AU - Hulgan, Todd

AU - Connor, James R.

AU - Jia, Peilin

AU - Zhao, Zhongming

AU - Letendre, Scott L.

AU - Ellis, Ronald J.

AU - Bush, William S.

AU - Samuels, David C.

AU - Franklin, Donald R.

AU - Kaur, Harpreet

AU - Iudicello, Jennifer

AU - Grant, Igor

AU - Kallianpur, Asha R.

PY - 2017/4/21

Y1 - 2017/4/21

N2 - Background: HIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND. Methods: We quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (QAlb) measurements, QAlb and comorbidity severity were also included as covariates to account for variability in the blood-CSF-barrier. Results: Among 403 individuals (median age 43 years, 19% women, 56% non-Whites, median nadir CD4+ T cell count 180 cells/μL, 46% with undetectable plasma virus), men had 25% higher CSF transferrin (median 18.1 vs. 14.5 μg/mL), and 71% higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41% higher in self-reported Hispanics and 27% higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 μg/dL in Hispanics and Whites, respectively, vs. 3.7 μg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25% higher (p < 0.05), and transferrin 14% higher (p = 0.06), in Whites than Blacks. Transferrin and H-ferritin were 33 and 50% higher, respectively, in older (age > 50 years) than in younger persons (age ≤ 35 years; both p < 0.01), but these findings lost statistical significance in subset analyses that adjusted for QAlb and comorbidity. After these additional adjustments, associations were observed for CSF iron and transferrin with race/ethnicity as well as CSF VL, for transferrin with sex and ART, and for H-ferritin with plasma virus detectability and significant comorbidity (all p < 0.05). Conclusions: CSF iron biomarkers are associated with demographic factors, ART, and CSF VL in HIV+ adults. Future studies should investigate a role for CNS iron dysregulation, to which an altered blood-CSF barrier may contribute, in HAND.

AB - Background: HIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND. Methods: We quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (QAlb) measurements, QAlb and comorbidity severity were also included as covariates to account for variability in the blood-CSF-barrier. Results: Among 403 individuals (median age 43 years, 19% women, 56% non-Whites, median nadir CD4+ T cell count 180 cells/μL, 46% with undetectable plasma virus), men had 25% higher CSF transferrin (median 18.1 vs. 14.5 μg/mL), and 71% higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41% higher in self-reported Hispanics and 27% higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 μg/dL in Hispanics and Whites, respectively, vs. 3.7 μg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25% higher (p < 0.05), and transferrin 14% higher (p = 0.06), in Whites than Blacks. Transferrin and H-ferritin were 33 and 50% higher, respectively, in older (age > 50 years) than in younger persons (age ≤ 35 years; both p < 0.01), but these findings lost statistical significance in subset analyses that adjusted for QAlb and comorbidity. After these additional adjustments, associations were observed for CSF iron and transferrin with race/ethnicity as well as CSF VL, for transferrin with sex and ART, and for H-ferritin with plasma virus detectability and significant comorbidity (all p < 0.05). Conclusions: CSF iron biomarkers are associated with demographic factors, ART, and CSF VL in HIV+ adults. Future studies should investigate a role for CNS iron dysregulation, to which an altered blood-CSF barrier may contribute, in HAND.

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