Blood-brain barrier integrity, intrathecal immunoactivation, and neuronal injury in HIV

Abstract

Objective: Although blood-brain barrier (BBB) impairment has been reported in HIV-infected individuals, characterization of this impairment has not been clearly defined.

Methods: BBB integrity was measured by CSF/plasma albumin ratio in this cross-sectional study of 631 HIV-infected individuals and 71 controls. We also analyzed CSF and blood HIV RNA and neopterin, CSF leukocyte count, and neurofilament light chain protein (NFL) concentrations. The HIV-infected participants included untreated neuroasymptomatic patients, patients with untreated HIV-associated dementia (HAD), and participants on suppressive antiretroviral treatment (ART).

Results: The albumin ratio was significantly increased in patients with HAD compared to all other groups. There were no significant differences between untreated neuroasymptomatic participants, treated participants, and controls. BBB integrity, however, correlated significantly with CSF leukocyte count, CSF HIV RNA, serum and CSF neopterin, and age in untreated neuroasymptomatic participants. In a multiple linear regression analysis, age, CSF neopterin, and CSF leukocyte count stood out as independent predictors of albumin ratio. A significant correlation was found between albumin ratio and CSF NFL in untreated neuroasymptomatic patients and in participants on ART. Albumin ratio, age, and CD4 cell count were confirmed as independent predictors of CSF NFL in multivariable analysis.

Conclusions: BBB disruption was mainly found in patients with HAD, where BBB damage correlated with CNS immunoactivation. Albumin ratios also correlated with CSF inflammatory markers and NFL in untreated neuroasymptomatic participants. These findings give support to the association among BBB deterioration, intrathecal immunoactivation, and neuronal injury in untreated neuroasymptomatic HIV-infected individuals.

Figure 1. CSF/plasma albumin ratio in the different groups of HIV-infected participants and the healthy controls

Boxes encompass interquartile ranges with median (line) and mean (+), while whiskers designate 10th to 90th percentiles. Included in this cross-sectional analyses were 71 controls (HIV−); HIV-infected neuroasymptomatic participants without antiretroviral treatment (ART) stratified according to levels of blood CD4+ T-cell count >350 (n = 125), 200–349 (n = 117), 50–199 (n = 102), and <50 (n = 71); 57 participants with HIV-associated dementia (HAD) staged according to severity of symptoms, stage 1 (n = 24) and stage 2–4 (n = 33); and 159 participants on ART ≥6 months and plasma HIV RNA <50 copies/mL. Albumin ratios were significantly higher in patients with HAD (stage 1–4 pooled) compared to all other groups (p < 0.001).

Figure 2. CSF biomarkers in HIV-infected untreated neuroasymptomatic participants with damaged and normal blood–brain barrier (BBB)

Comparisons of CSF biomarkers in HIV-infected untreated neuroasymptomatic participants with impaired (Alb ratio +) and normal (Alb ratio −) BBB function with respect to age-dependent reference values. CSF HIV RNA levels did not differ significantly between the groups (A) whereas CSF neopterin (p < 0.05, B) and CSF neurofilament light chain protein (NFL) (p < 0.01, C) were higher in participants with impaired BBB compared with those with normal BBB.