Date of Award

Spring 5-4-2016

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Ling Cao

Second Committee Member

Colin Willis

Third Committee Member

Gregory Cox

Additional Committee Members

Robert Burgess

Douglas Currie

Abstract

Nearly half of human immunodeficiency virus type 1 (HIV-1) patients experience cognitive impairments. These deficits coincide with inflammation and neurodegeneration in the hippocampus and striatum, brain regions important in memory formation. Opioid abuse accelerates the onset of HIV-associated neurocognitive deficits (HAND) by modulating the inflammatory response of microglia and astrocytes. These glial cells initiate and maintain innate immune defense in the central nervous system (CNS). Using the LP-BM5 murine acquired immunodeficiency (MAIDS) model, we investigated the region- and cell-specific effects of morphine on CNS viral infection and immune defense.

The LP-BM5 model offers an underutilized perspective in HIV study: it retains the context of a productive viral infection, virally-induced peripheral immunodeficiency, and regional differences in CNS viral entry and replication within a mouse model. To study chronic morphine’s effects in the LP-BM5 model, we infected 8-week-old male C57BL/6Ncr mice with 5x104 plaque-forming units of LP-BM5. Seven weeks after infection, mice were implanted with subcutaneous 25 mg morphine or placebo pellets. Using this model, we investigated the effects of one week of chronic morphine treatment on LP-BM5 infection and the glial immune response in three regions of interest in the CNS: the hippocampus, striatum, and frontal lobe.

Chronic morphine impaired cognitive performance in LP-BM5-infected mice, correlating to increased LP-BM5 viral RNA expression in the hippocampus. However, morphine treatment decreased viral RNA in the striatum. Morphine suppressed expression of the proinflammatory markers CCL5 and inducible nitric oxide synthase in all regions studied without a proportionate increase in anti-inflammatory markers. The hippocampus and striatum exhibited critical differential changes in the type 1 interferon (IFN) response, which activates cells’ inherent antiviral capabilities. Morphine treatment increased RNA expression of IFN-α and IFN-β in the striatum. In hippocampus, morphine and LP-BM5 downregulated expression of multiple type 1 IFN-related genes. By inhibiting the hippocampal type 1 IFN response, morphine impedes cells’ ability to ward off viral infection and suppress replication. This work furthers our understanding of opiates’ region-specific effects on CNS antiviral defense, opening new potential avenues for treatment in morphine-potentiated HAND.

Download

Share