Date of Award

January 2017

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Serena Spudich

Abstract

Abnormal blood brain barrier (BBB) permeability has been implicated in the neuropathogenesis of chronic HIV infection. As neurocognitive impairment can persist despite effective combination antiretroviral therapy (cART), it is possible that irreversible central nervous system (CNS) processes are initiated in early infection, before cART is typically initiated. We analyzed the natural history of BBB permeability in primary HIV infection (PHI), and the effects of cART initiated during this period. CSF:Serum albumin quotient (QAlb), a marker of BBB permeability, was measured in longitudinal observational studies of PHI. We analyzed trajectories of QAlb pre- and post-cART using mixed-effects models, and associations between QAlb and CSF neurofilament light chain (NFL), N-acetylaspartate:creatinine (NAA:Cr, a magnetic resonance spectroscopy biomarker for neuronal integrity), and neuropsychological testing. Age-adjusted QAlb was elevated in PHI vs. controls at baseline (n=106, median 91 days post infection, dpi; n=64; p=0.02). Before cART, QAlb increased over time in 84 participants with normal baseline QAlb (p=0.006), and decreased in 22 with high baseline QAlb (p=0.011). QAlb correlated at baseline and longitudinally with NFL (r=0.497, p<0.001; r=0.555, p<0.001) and NAA:Cr in parietal grey matter (r=-0.352, p=0.015, r=-0.387, p=0.008), but not neuropsychological performance. QAlb did not change after a median 398 days of cART initiated at 225 dpi (p=0.174). QAlb rises during early HIV, associates with neuronal injury, and does not significantly improve over a year of treatment. HIV BBB-associated neuropathogenesis may be initiated in early infection.

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This is an Open Access Thesis.

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