Date of Award

January 2013

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Serena Spudich

Subject Area(s)

Medicine, Neurosciences, Health sciences

Abstract

The use of antiretroviral therapy (ART) has shifted the neurological manifestations of HIV-1 infection toward mild but debilitating HIV-associated neurocognitive disorder (HAND). Through two studies, we sought to characterize neuronal injury during primary and chronic HIV infection and to describe its relationship with HAND.

The aim of the first study was to quantify cerebrospinal fluid (CSF) and neuroimaging biomarkers of neuronal injury in primary HIV infection (PHI). We compared CSF levels of neurofilament light chain (NFL), tau, and amyloid proteins in 92 subjects with PHI and 25 controls and examined relationships with disease progression and neuroinflammation, neuropsychological testing, and proton-magnetic resonance spectroscopy (MRS). We hypothesized that PHI is characterized by increased CSF NFL that correlates with neuronal inflammation, and that tau and amyloid levels are normal in PHI. NFL was elevated in PHI (p=0.0004) and correlated with CSF neopterin (r=0.38, p=0.0005), IP-10 (r=0.39, p=0.002), WBCs (r=0.32, p=0.004), and CSF:plasma albumin ratio (r=0.60, p<0.0001). NFL correlated with decreased N-acteylaspartate and glutamate in the anterior cingulate, frontal white matter, and parietal gray matter (r>0.30, p<0.05). Beta-amyloid was elevated in PHI (p=0.0005) and correlated with time infected (r=0.34, p=0.003). Neither marker correlated with neuropsychological abnormalities. T-tau and amyloid precursor proteins did not differ between groups.

The aim of the second study was to characterize HIV-infected patients with neuro-symptomatic CSF `escape,' defined as detectable CSF HIV RNA in the setting of treatment-suppressed plasma levels or CSF RNA >1 log higher than plasma RNA. We conducted a retrospective case series of virologically controlled HIV-infected patients on ART with progressive neurological abnormalities who were determined to have CSF `escape' at 4 urban medical centers in the United States and Europe. We recorded levels of CSF HIV RNA and inflammatory markers, clinical signs and symptoms, and magnetic resonance imaging (MRI) findings. We hypothesized that individuals with this condition would have inflammation in CSF and MRI studies, that CSF virus would be resistant to the ART regimen, and that symptoms would improve when ART was changed based upon central nervous system (CNS) drug penetration and resistance genotyping. 10 patients presented with sensory, motor, and cognitive abnormalities. Median CSF HIV RNA was 3900 copies/mL; median plasma HIV RNA was 62 copies/mL. Median CD4+ T cell count was 482 cells/mm3. All patients had been controlled <500 copies/mL for median 27.5 months and 5/10 had been suppressed <50 copies/mL for median 19.5 months. Patients were on a stable ART regimen for median 21 months. All had CSF pleocytosis or elevated CSF protein; 7/8 had MRI abnormalities; and 6/7 harbored CSF resistance mutations. Following optimization of ART, 8/9 patients improved clinically.

Although these processes occur at distinct time points in the disease, both neuronal injury during PHI and the development of symptomatic CSF `escape' in chronic, well-treated infection are associated with, and possibly caused by, mechanisms involving immune activation and inflammation within the CNS. The inflammatory milieu induced by the activity of HIV in invading cells and triggering an immune response has important implications throughout the time course of infection, and may be particularly important for understanding the pathophysiology of HAND.

Comments

This is an Open Access Thesis.

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