Blood-Brain Barrier Disruption Is Initiated During Primary HIV Infection and Not Rapidly Altered by Antiretroviral Therapy

Abstract

Background. We explored the establishment of abnormal blood-brain barrier (BBB) permeability and its relationship to neuropathogenesis during primary human immunodeficiency virus (HIV) infection by evaluating the cerebrospinal fluid (CSF) to serum albumin quotient (Q Alb ) in patients with primary HIV infection. We also analyzed effects of initiating combination antiretroviral therapy (cART).Methods. The Q Alb was measured in longitudinal observational studies of primary HIV infection. We analyzed trajectories of the Q Alb before and after cART initiation, using mixed-effects models, and associations between the Q Alb and the CSF level of neurofilament light chain (NFL), the ratio of N-acetylaspartate to creatinine levels (a magnetic resonance spectroscopy neuronal integrity biomarker), and neuropsychological performance.Results. The baseline age-adjusted Q Alb was elevated in 106 patients with primary HIV infection (median time of measurement, 91 days after infection), compared with that in 64 controls (P = .02). Before cART initiation, the Q Alb increased over time in 84 participants with a normal baseline Q Alb (P = .006) and decreased in 22 with a high baseline Q Alb (P = .011). The Q Alb did not change after a median cART duration of 398 days, initiated at a median interval of 225 days after infection (P = .174). The Q Alb correlated with the NFL level at baseline (r = 0.497 and P < .001) and longitudinally (r = 0.555 and P < .001) and with the ratio of N-acetylaspartate to creatinine levels in parietal gray matter (r = −0.352 and P < .001 at baseline and r = −0.387 and P = .008 longitudinally) but not with neuropsychological performance.Conclusion. The Q Alb rises during primary HIV infection, associates with neuronal injury, and does not significantly improve over a year of treatment. BBB-associated neuropathogenesis in HIV-infected patients may initiate during primary infection.

Longitudinal Trajectories of Brain Volume and Cortical Thickness in Treated and Untreated Primary Human Immunodeficiency Virus Infection

“…Future longitudinal studies are warranted to clarify whether structural atrophy is caused by the virus or confounded by ageing. These findings, along with reports from previous studies [5,[7][8][9]11,12,16], support the presumed initiation of HIV neuropathogenesis in early infection. The virus penetrates the CNS after initial systemic viral infection, infecting and activating local CNS immune cells [1].…”

“…These cells begin to release viral proteins and produce inflammatory factors resulting in prominent inflammation [5][6][7], immune activation and suppression [8][9][10], and BBB disruption [11], all of which facilitate neuronal injury and brain volume reduction [1,12,13,15]. If the infection remains untreated, we demonstrate here that brain atrophy and cortical thinning continues, while others report that markers of immune status, inflammation and BBB permeability progressively worsen [5,9,11]. Although the observed atrophy was not associated with any blood or CSF biomarkers, this could be an indication that a single biomarker is insufficient to infer underlying structural brain alterations; instead, a combination of these biomarkers may be more suitable for neurological prognosis.…”

“…It has been hypothesized that structural brain alterations may occur in primary HIV infection (PHI; defined as <1 year after exposure), possibly before cART initiation [3]. Several studies have demonstrated that prominent inflammation [5][6][7], immune activation [8][9][10] and blood-brain barrier (BBB) disruption [11] were evident during the first year of infection, and progressively worsened in the absence of cART [5,9,11]. All of these factors have been linked to neuronal injury during this period [12], and could contribute, in part, to brain volume reductions previously reported in PHI individuals [13][14][15].…”

Cognitive impairment and CSF proteome modification after oral bacteriotherapy in HIV patients

“…Moreover, TTR is important for thyroxine (T4) transfer from blood to CSF through the blood-brain barrier (BBB) and protects the brain from β-amyloid neurotoxic accumulations into amyloid plaques, commonly observed in the early stages of Alzheimer's disease and other disorders such as schizophrenia (Chen et al 2016;Richardson et al 2015). Among the abundant proteins at T0, we observed different protein species of albumin, consistent with Rahimy et al (2017) and also spots of hemoglobin α and β, which is physiologically absent, or present at very low levels, in healthy CSF. These results strongly suggest the presence of a BBB impairment, characterized by the loss of its selective competence to regulate molecule exchange between blood vessels and the CSF, independently of disease stadiation.…”

HIV-1 counteracts an innate restriction by amyloid precursor protein resulting in neurodegeneration

“…It is also worth noting that the few studies that do use primary human brain cells acquire material during biopsy or autopsy, meaning cells are isolated under pathological or trauma/hypoxic conditions that would likely alter microglia biology in unpredictable ways. However, primary rodent microglia do express APP 34 , and we were able to confirm APP expression and functionality in primary human peripheral blood mononuclear cells (PBMCs), the blood-stream counterparts of microglia that notably also enter the brain during HIV-1 infection 35 , 36 . Validating our overall findings, RNAi-mediated depletion of APP in PBMCs infected with WT HIV-1 resulted in a statistically significant increase in the production of extracellular HIV-1 particles (Fig.…”