This item is under embargo and not available online per the author's request. For access information, please visit http://libanswers.wustl.edu/faq/5640.

Title

HIV Neurodegeneration in the HAART Era

Date of Award

Spring 5-15-2015

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Human Immunodeficiency Virus (HIV) is known to cause HIV associated neurocognitive disorders (HAND), in HIV infected (HIV+) individuals. While highly active anti-retroviral therapy (HAART), has reduced the severity of HAND from a frank dementia to lesser impairments, the etiology and progression of neurodegeneration that leads to HAND is not clear. Plasma biomarkers of HIV damage (T-cell counts & viral copies/mL of blood) are no longer reliable correlates of HAND progression, due to complex relationships between effective HAART treatment and chronic inflammation due to HIV. Thus, neuroimaging research is necessary to unravel the progression of neurodegeneration, including the effects of confounding and modifying factors such as aging, HAART, and viral genetics. In the following studies, we used neuroimaging to assess these factors and their effects on structural and functional brain metrics.

First, using structural neuroimaging we confirmed that HIV associated neurodegeneration in the HAART era continues to affect white matter and subcortical areas predominantly. Using a piece-wise linear regression model we found that HIV infection imparts a gradual decline in a subcortical region (caudate). In a longitudinal HIV+ cohort scanned both prior to initiating HAART and at a 6-10 month follow-up, no significant changes to brain volumetrics were found. HIV continues to cause extensive neurodegeneration in the presence or absence of HAART.

We were fortunate to have collaborative data on HIV+ and HIV-uninfected (HIV-) individuals across two cohorts from St. Louis, and Cape Town, South Africa. Evolutionary pressures have created genetically distinct HIV clades, with variations in HIV/host pathogenesis. We used neuroimaging to assess whether HIV clade B [(HIV-B) from Saint Louis, USA] and HIV clade C [(HIV-C), from South Africa] had divergent neuropathogenicity at the brain structural level. HIV-B infected individuals had similar regional brain atrophy to HIV-C infected individuals. However, all HIV-C individuals were more impaired than HIV-B on brief cognitive tests. Generally, HIV appears to impart similar neurodegeneration, but HIV-C infected individuals may have increased cognitive impairments. Likely causes of this confound include socio-economic differences, language and cultural barriers that are not adequately controlled in neuropsychological tests. Since neuroimaging is bias-free of some of these variables, we aimed to use resting state functional connectivity MRI (rs-fcMRI) to assess HIV neurodegeneration across functional brain networks that reflect performance of cognitive tasks.

Rs-fcMRI has shown that HIV causes disruptions across several cortical networks, but subcortical contributions are unknown. We used rs-fcMRI to investigate the cortico-striatal networks across HIV+ and HIV- cohorts. Significant losses in coherence within default mode and ventral attention networks occurred in the HIV+. HAART was beneficial to specific regions of these networks, however cognitive function was not significantly improved for individuals on stable therapy. Future work on maximizing the benefit of HAART to both brain networks and cognition is necessary.

Despite HAART, HIV continues to exert neurodegeneration. Using advanced neuroimaging we found HIV imparts connectivity dysfunction in striato-cortical pathways of HIV+ individuals. Future studies are necessary to understand the topography and progression of neuropathogenesis.

Language

English (en)

Chair and Committee

Beau M Ances

Committee Members

Tammie Benzinger, Denise Head, David Clifford, Robert Paul, Joshua Shimony

Comments

Permanent URL: https://doi.org/10.7936/K7JM27SC

This document is currently not available here.

Share

COinS