Compartmentalization of cerebrospinal fluid inflammation across the spectrum of untreated HIV-1 infection, central nervous system injury and viral suppression.

Magnus Gisslen,Serena Spudich,Sheila M Keating,Richard W Price,Sophie Stephenson,Lars Hagberg,Victor Arechiga,Dietmar Fuchs,Philip J Norris,Barbara L Shacklett,Henrik Zetterberg,Constantin T Yiannoutsos,Kaj Blennow,Clara Di Germanio,Julia Peterson

doi:10.1371/journal.pone.0250987

Abstract

ObjectiveTo characterize the evolution of central nervous system (CNS) inflammation in HIV-1 infection applying a panel of cerebrospinal fluid (CSF) inflammatory biomarkers to grouped subjects representing a broad spectrum of systemic HIV-1 immune suppression, CNS injury and viral control.MethodsThis is a cross-sectional analysis of archived CSF and blood samples, assessing concentrations of 10 functionally diverse soluble inflammatory biomarkers by immunoassays in 143 HIV-1-infected subjects divided into 8 groups: untreated primary HIV-1 infection (PHI); four untreated groups defined by their blood CD4+ T lymphocyte counts; untreated patients presenting with subacute HIV-associated dementia (HAD); antiretroviral-treated subjects with ≥1 years of plasma viral suppression; and untreated elite controllers. Twenty HIV-1-uninfected controls were included for comparison. Background biomarkers included blood CD4+ and CD8+ T lymphocytes, CSF and blood HIV-1 RNA, CSF white blood cell (WBC) count, CSF/blood albumin ratio, CSF neurofilament light chain (NfL), and CSF t-tau.FindingsHIV-1 infection was associated with a broad compartmentalized CSF inflammatory response that developed early in its course and changed with systemic disease progression, development of neurological injury, and viral suppression. CSF inflammation in untreated individuals without overt HAD exhibited at least two overall patterns of inflammation as blood CD4+ T lymphocytes decreased: one that peaked at 200–350 blood CD4+ T cells/μL and associated with lymphocytic CSF inflammation and HIV-1 RNA concentrations; and a second that steadily increased through the full range of CD4+ T cell decline and associated with macrophage responses and increasing CNS injury. Subacute HAD was distinguished by a third inflammatory profile with increased blood-brain barrier permeability and robust combined lymphocytic and macrophage CSF inflammation. Suppression of CSF and blood HIV-1 infections by antiretroviral treatment and elite viral control were associated with reduced CSF inflammation, though not fully to levels found in HIV-1 seronegative controls.

Highlights

Infection of the central nervous system (CNS) is a nearly universal facet of untreated human immunodeficiency virus type 1 (HIV-1) infection and is accompanied by increased CNS immune activation and inflammation with frequent cerebrospinal fluid (CSF) lymphocytic pleocytosis and increased concentrations of a variety of inflammatory biomarkers [1,2,3,4,5,6,7,8,9,10,11]
Our main emphasis will be on the CSF inflammatory biomarker findings, while their blood counterparts will be considered mainly among the features of the background context to CNS inflammation
Among the major features of the broad and robust CSF inflammatory response were: 1. CSF biomarker concentrations varied in relation to their blood counterparts in absolute terms at ‘baseline’ (HIV negative) and in relative terms over the spectrum of HIV-1 disease; 2. the CSF inflammatory biomarkers exhibited higher concentrations in the untreated HIV-1-infected groups than in the uninfected controls in CSF, though the patterns of change across the groups differed among the biomarkers; 3. high CSF but not blood levels of all the markers were found in the HIV-associated dementia (HAD) group; and 4. viral suppression by antiretroviral treatment (ART) or by elite control reduced the CSF biomarker elevations, though not always to levels found in the HIV-negative controls

Summary

Introduction

Infection of the central nervous system (CNS) is a nearly universal facet of untreated human immunodeficiency virus type 1 (HIV-1) infection and is accompanied by increased CNS immune activation and inflammation with frequent cerebrospinal fluid (CSF) lymphocytic pleocytosis and increased concentrations of a variety of inflammatory biomarkers [1,2,3,4,5,6,7,8,9,10,11]. CSF HIV-1 may be predominantly sustained in CD4+ T-lymphocytes (T-tropic) with CSF HIV-1 populations genetically similar to those circulating in blood [26], presumably as a result of CD4+ T-cell traffic that carries both infected and uninfected target CD4+ T cells into the CNS [26, 27]. In the setting of advanced systemic infection, frank HIV-1 encephalitis may cause severe brain dysfunction and a syndrome that was initially termed subacute encephalitis [32] and AIDS dementia complex (ADC) [33, 34], and is encompassed within the term HIV-associated dementia (HAD) [35] Through these different stages of systemic and CNS disease progression and suppression, the character of CSF inflammation may vary. CSF t-tau levels, previously reported, were measured by published methods [41]

Methods

Results

Conclusion