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

• DOI: 10.1371/journal.pone.0250987
• Publication Date: 2021-05-13T17:44:26Z
• Authors: Magnus Gisslen; Sheila M. Keating; Serena Spudich; Victor Arechiga; Sophie Stephenson; Henrik Zetterberg; Clara Di Germanio; Kaj Blennow; Dietmar Fuchs; Lars Hagberg; Philip J. Norris; Julia Peterson; Barbara L. Shacklett; Constantin T. Yia...; Richard W. Price
• Keywords: CD4-Positive T-Lymphocytes; Central Nervous System; Male; Pediatric AIDS; Sustained Virologic Response; HIV Infections; CD8-Positive T-Lymphocytes; Leukocyte Count; 0302 clinical medicine; Neurofilament Proteins; Antiretroviral Therapy, Highly Active; 2.1 Biological and endogenous factors; Viral; Aetiology; Pediatric; Q; R; Neurofilament proteins; Middle Aged; 3. Good health; Infectious Diseases; Anti-Retroviral Agents; Medical Microbiology; 6.1 Pharmaceuticals; HIV/AIDS; Medicine; RNA, Viral; Female; Infection; HIV infections; Research Article; Adult; General Science & Technology; Science; Immunology; 610; Antiretroviral Therapy; Anti-retroviral agents; 03 medical and health sciences; Clinical Research; 616; Acquired Cognitive Impairment; Humans; Highly Active; Serum Albumin; Inflammation; Biomedical and Clinical Sciences; Inflammatory and immune system; Neurosciences; Evaluation of treatments and therapeutic interventions; Brain Disorders; Good Health and Well Being; Cross-Sectional Studies; Central nervous system; HIV-1; RNA; Biomarkers

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.