Alcohol as a catalyst for hiv-associated neuroinflammation and tbi-induced iron toxicity

Author

Agnieszka Agas, New Jersey Institute of Technology

Document Type

Dissertation

Date of Award

8-30-2021

Degree Name

Doctor of Philosophy in Biomedical Engineering - (Ph.D.)

Department

Biomedical Engineering

First Advisor

James Haorah

Second Advisor

Kevin D. Belfield

Third Advisor

Pranela Rameshwar

Fourth Advisor

Jiang-Hong Ye

Fifth Advisor

Vivek A. Kumar

Abstract

Alcohol has long been considered an exacerbator of diseases, disorders, and injuries as well as many of the accompanying symptoms. As an alternative approach, this dissertation explores alcohol as a catalyst for two different human disease conditions, human immunodeficiency virus (HIV)-associated neuroinflammation and traumatic brain injury (TBI)-induced iron toxicity. In HIV-1 infection, this dissertation presents a novel anti-viral drug, called Drug-S, for a possible inhibition and treatment of HIV-1 disease progression.

The first aim explores the influence of alcohol with HIV-associated neuroinflammation on macrophage migration across an in vitro model of the blood brain barrier. There is a gap in knowledge on the effects of low dose alcohol under HIV-associated injury in people living with HIV-1 who have achieved viral suppression. The model, consisting of a quad-cultivation of neuroimmune cells including endothelial, astrocyte, macrophage, and neuron cells, is challenged with low dose (10 mM) alcohol and the viral protein trans-activator of transcription (TAT). It was then observed for changes to barrier integrity and neuronal injury upon macrophage migration. Results show that combined alcohol and viral injuries significantly increases migration even under the clinically lowest concentrations of alcohol. The cause of enhanced macrophage migration and related neurotoxicity is implicated to alcohol-induced nitric oxide production by endothelial cells and TAT's chemoattractant properties.

The second aim analyzes a compound called Drug-S as a possible therapeutic for inhibiting HIV-1 replication and HIV-1 disease progression. Although the combination of highly active antiretroviral therapy can remarkably control HIV-1, it is not a cure. Current therapy is unable to eliminate persistent HIV-1 contained in latent reservoirs in the central nervous system and to prevent rebound viral replication and resurgence when treatment is withdrawn. Treating HIV-1 infected macrophage with Drug-S shows inhibition of infection and persistence at a low concentration without causing any toxicity to neuroimmune cells. Results suggest that Drug-S may have a direct effect on viral structure, prevent rebounding of HIV-1 infection, and arrest progression into acquired immunodeficiency syndrome.

The third aim explores the role of low level of alcohol use in TBI-induced hemolytic iron management. As hemorrhage is a major component of TBI, the accumulated red blood cells in the tissue layers undergo hemolysis and release free iron into the central nervous system. As a secondary stressor, prior alcohol consumption can increase iron aggregation and alter its management. The effects of alcohol on TBI- induced iron toxicity is explored in an in vivo model of chronic alcohol exposure subjected to fluid percussion injury. Results show that alcohol increases the iron overload and alters iron management following injury by changing the expression profile of the iron regulatory proteins lipocalin 2, heme oxygenase 1, ferritin light chain, and hemosiderin. Accompanying these results, it was also found that microglia can similarly play a significant role in iron management by phagocytosing red blood cells and retaining iron.

Overall, the results of this dissertation demonstrate the pervasive impact of alcohol use in neuropathophysiology arising from HIV protein TAT toxicity or TBI-induced iron toxicity. In addition, the newly discovered DrugS can be an effective antiviral drug for a possible HIV/AIDS disease prevention and progression.

Recommended Citation

Agas, Agnieszka, "Alcohol as a catalyst for hiv-associated neuroinflammation and tbi-induced iron toxicity" (2021). Dissertations. 1654.
https://digitalcommons.njit.edu/dissertations/1654