Abstract
BackgroundCentral 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.ResultsAfter 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.ConclusionsAdvanced 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.
Highlights
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
cerebrospinal fluid (CSF) analysis has shown that the clinical manifestations of chronic CNS infection range from common asymptomatic infection, often accompanied by clinically silent CSF pleocytosis [5], to more severe “invasive” HIV encephalitis (HIVE) presenting clinically as the AIDS dementia complex (ADC) [7,8], most commonly referred to as HIV seronegative (HIV-)associated dementia (HAD) [9]
Analysis of the CSF proteome of HIV infected individuals prior to and coincident with combination antiretroviral therapy (cART) allowed the analysis of a wide range of disease severity in a relatively small number of samples
Summary
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. While central nervous system (CNS) HIV infection is a nearly universal facet of systemic infection, its course and clinical manifestations are highly variable and, evolve over time within individual patients. CNS infection can be detected soon after primary exposure and initial viremia [1,2], and continues throughout the chronic course of untreated infection [3,4,5,6] This course has been defined to a great extent by studies of cerebrospinal fluid (CSF), which provides a useful window into CNS infection and disease. While combination antiretroviral therapy (cART) has been very effective in reducing the incidence of severe HAD [12,13], milder neurological impairment is noted in otherwise well-treated populations [14,15,16] and is of particular concern as surviving patients age [17]
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