CSF Inflammation Markers Associated with Asymptomatic Viral Escape in Cerebrospinal Fluid of HIV-Positive Individuals on Antiretroviral Therapy

Abstract

HIV establishes a viral reservoir in the CNS despite viral suppression in the blood on antiretroviral therapy (ART). In a minority of people with HIV (PWH), HIV RNA is detectable in CSF when HIV RNA in plasma is undetectable or HIV RNA levels are higher in CSF compared with plasma, an event termed CSF viral escape that can occur with or without neurological symptoms. Asymptomatic CSF viral escape occurs in 3–20% of PWH on ART, yet associated biomarkers are unclear. To identify biomarkers associated with asymptomatic CSF viral escape, we performed a matched group study of PWH on ART with vs. without CSF viral escape (n = 10 and n = 60, respectively, matched for age, duration of HIV infection, nadir CD4 count, and ART regimen) and 50 HIV-negative controls. PWH were on 3 or more ART drugs for >1 year, and the group with no CSF viral escape was suppressed below 50 copies/mL in plasma and CSF. Biomarkers of inflammation (IFN-γ, IL-1β, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF), cell adhesion (ICAM-1, VCAM-1), CNS injury (NFL), and glial activation (GFAP, YKL-40) were measured in paired plasma and CSF using the Meso Scale Discovery platform. PWH with vs. without CSF viral escape had more individuals (40%) with a plasma viral load (VL) > 50 copies/mL, higher CSF VL (median 156 vs. 40 copies/mL; p < 0.0001), lower CD4 count (318 vs. 512; p = 0.045), and higher CSF WBC (median [IQR] 4 [0–22] vs. 2 [0–4] cells/µL; p = 0.15) but similar proportions with HIV-associated neurocognitive disorders (HAND) (50% vs. 47%). CSF viral escape was associated with increased IL-1β, IFN-γ, IP-10, ICAM-1, and VCAM-1 in CSF but not plasma; IP-10 had the strongest association (p = 0.0008). CSF VL and WBC correlated with IFN-γ, IP-10, ICAM-1, and VCAM-1 (p < 0.05). Although markers of CNS injury showed no significant association with asymptomatic CSF viral escape, CSF YKL-40 correlated positively with CSF IL-1β (p = 0.003), IFN-γ (p = 0.0008), IP-10 (p < 0.0001), and NFL (p = 0.06) and negatively with neurocognitive T scores (p = 0.02). These findings identify CSF inflammation and glial activation markers that may serve as surrogate measures of HIV persistence in the CNS for future studies on therapeutics targeting the CNS reservoir.

IL-10 predicts incident neuroinflammatory disease and proviral load dynamics in a large Brazilian cohort of people living with human T-lymphotropic virus type 1

“…Because of the striking findings of low IL-10 and IL-4 as independent risk factors for iHAM, and the predictive power of IL-10 for posterior PVL dynamics, we further explored the possible upstream and downstream mechanisms by examining a large panel of 37 pro-and anti-inflammatory cytokines, chemokines and immune mediators. Of those 37, seven were previously suggested as candidate biomarkers and/or therapeutic targets (MMP-1/2/3, TNFR1/2, IL-22, Osteopontin) ( 16 – 24 ) in HAM, while most of them were not previously interrogated at the protein level in HAM patients but have been demonstrated in other neuroinflammatory or neurodegenerative disorders, such as CHI3L1 (also known as YKL-40) in HIV-Associated Neurocognitive Decline (HAND) ( 25 ). Since only 64 out of 110 plasma samples were available (of which 6/9 iHAM) for these additional assays, we considered this an exploratory analysis because of the lower sample size.…”

Multi-modal analysis of inflammation as a potential mediator of depressive symptoms in young people with HIV: The GOLD depression study

“…Hermansson et al [ 32 ] found that YKL-40 concentrations in CSF did not differ between participants with and without HIV. Guha and colleagues [ 33 ] recently also observed no significant difference in plasma or CSF concentrations of YKL-40 by HIV status, but significantly higher YKL-40 in CSF (compared to people without HIV) specifically in people with HIV with a CSF HIV viral load higher than 50 copies/mL [ 34 ]. Notably, these studies were carried out in older adults.…”

Effects of antiretroviral treatment on central and peripheral immune response in mice with EcoHIV infection

“…HIV infection is associated with immune responses that include increased circulating cytokine levels in the periphery and within the central nervous system (CNS), and which may contribute to severity of disease (Merrill and Chen, 1991). Although ART can effectively maintain HIV-1 viral load at undetectable levels and prolong lifespan of PLWH, ART does not completely eliminate infection or the impact of HIV-induced immune response peripherally or within the central nervous system (CNS) on comorbidities including HIV-associated neurocognitive disorder (HAND) (Valcour et al, 2012;Ripamonti and Clerici, 2021;Guha et al, 2023).…”