Blood–Brain Barrier Impairment in Patients Living with HIV: Predictors and Associated Biomarkers

Abstract

Despite the substantial changes resulting from the introduction of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders (HAND) remains substantial. Blood–brain barrier impairment (BBBi) is a frequent feature in people living with HIV (PLWH) and it may persist despite effective antiretroviral treatment. A cross-sectional study was performed in PLWH who underwent lumbar puncture for clinical reasons or research protocols and several cerebrospinal fluid biomarkers were studied. BBBi was defined as cerebrospinal fluid-to-serum albumin ratio (CSAR) >6.5 (<40 years) or >8 (>40 years). We included 464 participants: 147 cART-naïve and 317 on cART. Male sex was prevalent in both groups (72.1% and 72.2% respectively); median age was 44 (38–52) years in naïve and 49 (43–57) years in treated subjects. BBBi was observed in 35.4% naïve and in 22.7% treated participants; the use of integrase inhibitors was associated with a lower prevalence (18.3 vs. 30.9%, p = 0.050). At multivariate binary logistic regression (including age and sex) nadir CD4 cell count (p = 0.034), presence of central nervous system (CNS) opportunistic infections (p = 0.024) and cerebrospinal fluid (CSF) HIV RNA (p = 0.002) in naïve participants and male sex (p = 0.021), a history of CNS opportunistic infections (p = 0.001) and CSF HIV RNA (p = 0.034) in treated patients were independently associated with BBBi. CSF cells and neopterin were significantly higher in participants with BBBi. BBBi was prevalent in naïve and treated PLWH and it was associated with CSF HIV RNA and neopterin. Systemic control of viral replication seems to be essential for BBB integrity while sex and treatment influence need further studies.

Neuroimmunology of CNS HIV Infection: A Narrative Review

“…Likely the external toxic signals are elaborated mainly from inflammatory cells, perhaps predominantly from macrophages and other myeloid cells. Late in infection HIVE also commonly disrupts the blood-brain barrier, further contributing to neuronal injury and dysfunction ( 36 , 88 , 89 ).…”

Plasma biomarkers of vascular dysfunction uniquely relate to a vascular-risk profile of neurocognitive deficits in virally-suppressed adults with HIV

“…Recent studies have also found evidence of endothelial dysfunction and blood-brain barrier (BBB) impairment in ART-treated and virally-suppressed PWH ( Caligaris et al, 2021 ; Ellis et al, 2021 ; Gelman, 2015 ; Kristoffersen et al, 2009 ; Melendez et al, 2008 ; Ross et al, 2009 ). The BBB, composed of specialized endothelial cells and tight junctions and surrounded by a basement membrane, pericytes, astrocytes, microglia and neurons ( Atluri et al, 2015 ; De Benedetto et al, 2020 ; Marincowitz et al, 2019 ), is a primary target of HIV-associated neural injury ( Eugenin et al, 2006 ; Williams et al, 2012 ) and a central neuropathological factor underlying HAND ( Cysique and Brew, 2019 ; Gelman, 2015 ; Gelman et al, 2012 ).…”

Cerebrospinal Fluid Viral Load Across the Spectrum of Untreated Human Immunodeficiency Virus Type 1 (HIV-1) Infection: A Cross-Sectional Multicenter Study

“…In these patients, CSF HIV-RNA was also associated with albumin ratio, an association that was not as evident in the other groups ( Supplementary Figure 2 ). This might either be a reflection of facilitated penetration of peripheral virions into the CNS or that blood brain barrier impairment leads to an increased inflammatory response resulting in higher levels of locally replicated virus [ 28 ]. CSF HIV-RNA in the CNS OI group was also weakly associated with CSF pleocytosis, a finding previously observed in smaller studies [ 29 , 30 ] and in other CNS coinfections such as neuroborreliosis and herpes zoster [ 20 , 31 ].…”