Abstract
Human immunodeficiency virus-1 (HIV-1) infection of the nervous system can result in neuroinflammatory events leading first to neuronal dysfunction then to cognitive and behavioral impairments in infected people. The multifaceted nature of the disease process, commonly called HIV-1-associated dementia (HAD), provides a number of adjunctive therapeutic opportunities. One proposed adjunctive therapy is sodium valproate (VPA), an anticonvulsant known to promote neurite outgrowth and increase beta-catenin through inhibiting glycogen synthase kinase 3beta activity and tau phosphorylation. We now show that VPA treatment of rat cortical neurons exposed to HIV-1 gp120 prevents resultant neurotoxic activities. This includes the induction of significant neurite outgrowth and microtubule-associated protein 2 (MAP-2) and neuron-specific nuclear protein (NeuN) antigens in affected neuronal cell bodies and processes. Similarly, VPA protects severe combined immunodeficient (SCID) mice against the neurodegeneration of HIV-1ADA infected monocyte-derived macrophages (MDMs). In SCID mice with HIV-1 MDM-induced encephalitis, VPA treatment significantly reduced neuronal phosphorylatedbeta-catenin and tau without affecting HIV-1 replication or glial activation. We conclude that VPA protects neurons against HIV-1 infected MDM neurotoxicity, possibly through its effects on the phosphorylation of tau and beta-catenin. The use of VPA as an adjuvant in treatment of human HAD is being pursued.
Highlights
Progressive human immunodeficiency virus type one (HIV-1) infection leads to immune suppression and to a constellation of CNS disorders (Gendelman et al, 2003)
Immunopathology Human HIV-1ADA-infected monocytederived macrophages (MDMs) were stereotactically injected into the basal ganglia of severe combined immunodeficient (SCID) mice
We have shown the early manifestation of glial fibrillary acidic protein (GFAP) expression soon after implantation of Human immunodeficiency virus-1 (HIV-1)-infected MDMs into SCID mouse brains
Summary
Progressive human immunodeficiency virus type one (HIV-1) infection leads to immune suppression and to a constellation of CNS disorders (Gendelman et al, 2003). In its most severe form, cognitive, motor, and behavior abnormalities predominate and are termed HIV-1-associated dementia (HAD). The pathological hallmark of HAD is HIV-1 encephalitis (HIVE). HIVE is characterized by the accumulation of virus-infected multinucleated giant cells in white and deep gray matter, along with myelin pallor and astrocytosis. A unique feature of HIVE is that the principal viral target cell in the brain is not the neuron but the mononuclear phagocyte (MP; microglia and perivascular macrophages)
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