The cerebrospinal fluid proteome in HIV infection: change associated with disease severity

Clinical Proteomics

Henrik Zetterberg⁵  Jon M Jacobs¹  Marina A Gritsenko¹  Teri Liegler²  Richard D Smith¹  Thomas E Angel¹  Serena S Spudich⁴  David G Camp¹  Dietmar Fuchs³  Richard W Price² 

[1] Biological Sciences Division, Pacific Northwest National Laboratory, Richland, USABiological Sciences Division, Pacific Northwest National Laboratory, Richland, USABiological Sciences Division, Pacific Northwest National Laboratory, Richland, USA;University of California San Francisco, San Francisco, USAUniversity of California San Francisco, San Francisco, USAUniversity of California San Francisco, San Francisco, USA;Biocenter, Innsbruck Medical University, Innsbruck, AustriaBiocenter, Innsbruck Medical University, Innsbruck, AustriaBiocenter, Innsbruck Medical University, Innsbruck, Austria;University of California San Francisco, San Francisco, USAYale University School of Medicine, New Haven, USAUniversity of California San Francisco, San Francisco, USAUniversity of California San Francisco, San Francisco, USAYale University School of Medicine, New Haven, USAYale University School of Medicine, New Haven, USAUniversity of California San Francisco, San Francisco, USAYale University School of Medicine, New Haven, USA;Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenInstitute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, SwedenInstitute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden

关键词: Amyloid;    Cerebrospinal fluid;    HIV;    Pathway;    Proteomics;   

DOI  :  10.1186/1559-0275-9-3

来源: Humana Press Inc

【 摘 要 】

Abstract

Background

Central nervous system (CNS) infection is a nearly universal feature of untreated systemic HIV infection with a clinical spectrum that ranges from chronic asymptomatic infection to severe cognitive and motor dysfunction. Analysis of cerebrospinal fluid (CSF) has played an important part in defining the character of this evolving infection and response to treatment. To further characterize CNS HIV infection and its effects, we applied advanced high-throughput proteomic methods to CSF to identify novel proteins and their changes with disease progression and treatment.

Results

After establishing an accurate mass and time (AMT) tag database containing 23,141 AMT tags for CSF peptides, we analyzed 91 CSF samples by LC-MS from 12 HIV-uninfected and 14 HIV-infected subjects studied in the context of initiation of antiretroviral therapy and correlated abundances of identified proteins a) within and between subjects, b) with all other proteins across the entire sample set, and c) with "external" CSF biomarkers of infection (HIV RNA), immune activation (neopterin) and neural injury (neurofilament light chain protein, NFL). We identified a mean of 2,333 +/- 328 (SD) peptides covering 307 +/-16 proteins in the 91 CSF sample set. Protein abundances differed both between and within subjects sampled at different time points and readily separated those with and without HIV infection. Proteins also showed inter-correlations across the sample set that were associated with biologically relevant dynamic processes. One-hundred and fifty proteins showed correlations with the external biomarkers. For example, using a threshold of cross correlation coefficient (Pearson's) ≤ -0.3 and ≥0.3 for potentially meaningful relationships, a total of 99 proteins correlated with CSF neopterin (43 negative and 56 positive correlations) and related principally to neuronal plasticity and survival and to innate immunity. Pathway analysis defined several networks connecting the identified proteins, including one with amyloid precursor protein as a central node.

Conclusions

Advanced CSF proteomic analysis enabled the identification of an array of novel protein changes across the spectrum of CNS HIV infection and disease. This initial analysis clearly demonstrated the value of contemporary state-of-the-art proteomic CSF analysis as a discovery tool in HIV infection with likely similar application to other neurological inflammatory and degenerative diseases.

【 授权许可】

Unknown