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The impact of HIV-1 and mu-opioids on the bone marrow and blood-brain barrier
Dissertation   Open access

The impact of HIV-1 and mu-opioids on the bone marrow and blood-brain barrier

Marianne Strazza
Doctor of Philosophy (Ph.D.), Drexel University
May 2013
DOI:
https://doi.org/10.17918/00008489
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Abstract

Genetics Molecular Biology
One third of AIDS cases in the United States are attributable to injection drug use, a significant predisposing risk factor to contracting HIV-1. In addition to the increased risk of exposure, there is accumulating evidence that levels of drug in circulation can impact HIV-1 disease progression and neuropathogenesis. Opioid exposure in vivo and in vitro result in increased HIV replication in monocytes and CD4+ T cells. In the simian immunodeficiency virus (SIV) in vivo model, increased replication rate, viral load, and frequency of mutation in the periphery along with increased viral load detected in the cerebrospinal fluid (CSF) were observed in animals treated with opioids. Epidemiological studies have indicated an increased incidence of HIV-associated neurocognitive disorders (HAND) in patients abusing drugs. Additionally, opioids have been shown to potentiate HIV protein mediated neurotoxicity. Two classifications of HAND existed in the early stages of the HIV epidemic: HIV-associated dementia (HAD) and minor cognitive motor disorder. Approximately 15% of individuals infected with HIV-1 developed HAD, and approximately 30% to 60% of individuals developed less severe forms of HAND. Although highly active antiretroviral therapy (HAART) has increased survival, reduced viral loads, increased CD4 cell counts, and reduced opportunistic infections, one outcome has not changed: HAND is still a serious concern. Although the incidence of the most severe form of HAND, HAD, has decreased, the overall prevalence of HAND has not declined, potentially because patients with the more mild forms of HAND, are living longer with persistent impairment. While the mechanism underlying increased onset and severity of HAND in an opioid abusing population is not fully understood, it likely involves accelerating the overcoming of the major obstacle to viral neuropathogenesis, the blood-brain barrier (BBB). This can likely be attributed to dysregulation within the bone marrow, the origin of circulating cells within the periphery, and at the site of entry of this population into the CNS, the BBB. Damage to the BBB allows increased transendothelial migration from peripheral circulation, increasing the access of virally infected cells, viral proteins, and free virus to the central nervous system (CNS). These studies show that mu-opioids alter hematopoietic progenitor cell susceptibility to HIV-1 infection within the bone marrow through decreased surface expression of CXCR4. In addition, prolonged exposure of the endothelial cells that comprise the BBB to morphine increases firm adhesion and transmigration of a subpopulation of PBMCs across the BBB through a mechanism involving increased surface expression of cellular adhesion molecules. These studies suggest that morphine influences HIV-1 neuropathogensis on multiple fronts.

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