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

Abstract

Objective To 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. Methods This 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. Findings HIV-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.

Viral Antigen and Inflammatory Biomarkers in Cerebrospinal Fluid in Patients With COVID-19 Infection and Neurologic Symptoms Compared With Control Participants Without Infection or Neurologic Symptoms

“…Altogether, these findings indicate that the CNS immune response may be an important driver of CNS pathogenesis, similar to other CNS inflammatory conditions or infections. 11 , 13 , 29 , 38 The principal difference between patient groups appeared to be in the magnitude of the immune response, suggesting that neuropathogenesis in COVID-19 with neurologic symptoms represents a continuum of inflammation, where the intensity of the inflammatory response (likely in combination with individual premorbid vulnerability) may be a determining factor in the development of CNS symptoms. In turn, CNS symptoms may reflect harmful effects on the brain measurable as neuroaxonal injury (CSF NfL).…”

Neuroimmunology of CNS HIV Infection: A Narrative Review

“…Among the viruses considered in this collection, HIV likely has the most complex and intimate interactions with the immune system and inflammatory responses, both outside (i.e., systemically) and within the CNS. In both systemic and CNS compartments these interactions change over the long course of chronic infection ( 36 , 37 ). Figure 1 diagrams these interactions, dividing the systemic (left) from CNS (right) processes.…”

Blood biomarkers for HIV infection with focus on neurologic complications—A review

“…Studies on chemokine receptor type 2 on monocyte subsets of CD14 and CD 16 suggested those as prognostic peripheral blood biomarkers of HIV‐associated neurocognitive disorders 23 and neuronal damage, 24 while higher number of activated CD8+T lymphocytes and natural killer cells were associated with lower risk of depression 25 . In a recent study of several biomarkers, blood sCD14 and neopterin correlated strongly with CSF NfL and may be helpful in predicting CNS injury 26 . Blood C‐reactive protein (CRP) has also been reported as marker for risk of cognitive impairment.…”

“…25 In a recent study of several biomarkers, blood sCD14 and neopterin correlated strongly with CSF NfL and may be helpful in predicting CNS injury. 26 Blood C-reactive protein (CRP) has also been reported as marker for risk of cognitive impairment. In one study, variability in C-reactive protein was associated with cognitive impairment in women living with HIV.…”