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Elevated cerebrospinal fluid Galectin-9 is associated with central nervous system immune activation and poor cognitive performance in older HIV-infected individuals

  • Thomas A. Premeaux
  • Michelle L. D’Antoni
  • Mohamed Abdel-Mohsen
  • Satish K. Pillai
  • Kalpana J. Kallianpur
  • Beau K. Nakamoto
  • Melissa Agsalda-Garcia
  • Bruce Shiramizu
  • Cecilia M. Shikuma
  • Magnus Gisslén
  • Richard W. Price
  • Victor Valcour
  • Lishomwa C. NdhlovuEmail author
Article

Abstract

We previously reported that galectin-9 (Gal-9), a soluble lectin with immunomodulatory properties, is elevated in plasma during HIV infection and induces HIV transcription. The link between Gal-9 and compromised neuronal function is becoming increasingly evident; however, the association with neuroHIV remains unknown. We measured Gal-9 levels by ELISA in cerebrospinal fluid (CSF) and plasma of 70 HIV-infected (HIV+) adults stratified by age (older > 40 years and younger < 40 years) either ART suppressed or with detectable CSF HIV RNA, including a subgroup with cognitive assessments, and 18 HIV uninfected (HIV−) controls. Gal-9 tissue expression was compared in necropsy brain specimens from HIV− and HIV+ donors using gene datasets and immunohistochemistry. Among older HIV+ adults, CSF Gal-9 was elevated in the ART suppressed and CSF viremic groups compared to controls, whereas in the younger group, Gal-9 levels were elevated only in the CSF viremic group (p < 0.05). CSF Gal-9 positively correlated with age in all groups (p < 0.05). CSF Gal-9 tracked with CSF HIV RNA irrespective of age (β = 0.33; p < 0.05). Higher CSF Gal-9 in the older viremic HIV+ group correlated with worse neuropsychological test performance scores independently of age and CSF HIV RNA (p < 0.05). Furthermore, CSF Gal-9 directly correlated with myeloid activation (CSF-soluble CD163 and neopterin) in both HIV+ older groups (p < 0.05). Among HIV+ necropsy specimens, Gal-9 expression was increased in select brain regions compared to controls (p < 0.05). Gal-9 may serve as a novel neuroimmuno-modulatory protein that is involved in driving cognitive deficits in those aging with HIV and may be valuable in tracking cognitive abnormalities.

Keywords

Galectin-9 HIV Biomarkers Neuroinflammation Cognitive disorders 

Notes

Acknowledgements

We thank all study participants and study groups, Scott Bowler for his help with specimen management, and Vedbar Khadka, Daniel Laspisa, and Lindsay Kohorn for their guidance with data analysis.

Authors’ contributions

TAP and LCN drafted the manuscript. TAP performed all soluble analyte quantifications and data analyses. LCN conceived the design of the study and coordinated the integration of collaboration between all participating groups. MAM and SKP aided in the study design. BS and MAG conducted HIV DNA quantifications. VV, CMS, RKP, and MG designed the study cohorts and acquisition of participant demographic and clinical data. BKN and KK assisted with interpreting clinical and diagnostic data. VV, BS, MAM, and MLD provided critical analysis of the manuscript. All authors critically reviewed and edited the final version of the manuscript.

Funding

This work was supported in part by National Institutes of Health (NIH) grants 1R01MH112457-01 (LCN and SP), U54NS43049 (CS), MH098759 (VV), R01 NS094067 (RWP), P01 DA026134 (RWP, Project PI), and the Swedish State support for Clinical Research (ALFGBG-717531). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This publication was also made possible by NIH funding through the NIMH and NINDS institutes by the following grants: Texas NeuroAIDS Research Center: U24MH100930, California NeuroAIDS Tissue Network: U24MH100928, National Neurological AIDS Bank: U24MH100929, Manhattan HIV Brain Bank: U24MH100931, and Data Coordinating Center: U24MH100925. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NNTC or NIH.

Compliance with ethical standards

Ethics approval and consent to participate

Informed consent was obtained from participants following procedures approved by the University of Hawai’i Human Studies Institutional Review Board, UCSF Committee on Human Research, and the Regional Ethics Review Board in Gothenburg.

Conflict of interest

The authors declare that they have no competing interests.

Supplementary material

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Figure S1 Gal-9 correlates with indices of HIV disease progression. (a) Correlations between CSF and plasma Gal-9 levels and CD4 T cell counts. (b) CSF and plasma Gal-9 correlations with PBMC-associated HIV DNA levels. Associations between variables were analyzed by Spearman correlations. Statistical significance is indicated as *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001. (JPG 2156 kb)

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Copyright information

© Journal of NeuroVirology, Inc. 2018

Authors and Affiliations

  • Thomas A. Premeaux
    • 1
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  • Michelle L. D’Antoni
    • 1
    • 2
  • Mohamed Abdel-Mohsen
    • 3
  • Satish K. Pillai
    • 4
  • Kalpana J. Kallianpur
    • 1
    • 2
  • Beau K. Nakamoto
    • 2
    • 5
  • Melissa Agsalda-Garcia
    • 2
  • Bruce Shiramizu
    • 2
  • Cecilia M. Shikuma
    • 2
  • Magnus Gisslén
    • 6
  • Richard W. Price
    • 7
  • Victor Valcour
    • 8
  • Lishomwa C. Ndhlovu
    • 1
    • 2
    Email author
  1. 1.Department of Tropical Medicine, Medical Microbiology & Pharmacology, John A. Burns School of MedicineUniversity of Hawai’iHonoluluUSA
  2. 2.Hawai’i Center for AIDS, John A. Burns School of MedicineUniversity of Hawai’iHonoluluUSA
  3. 3.The Wistar InstitutePhiladelphiaUSA
  4. 4.Blood Systems Research InstituteSan FranciscoUSA
  5. 5.Straub Medical CenterHonoluluUSA
  6. 6.Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska AcademyUniversity of GothenburgGothenburgSweden
  7. 7.Department of NeurologyUniversity of California San FranciscoSan FranciscoUSA
  8. 8.Memory and Aging Center, Department of NeurologyUniversity of CaliforniaSan FranciscoUSA

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