Background:  HIV-1-infected and immune competent mononuclear phagocytes (MP; perivascular monocyte-derived brain macrophages and microglia) and astrocytes drive metabolic and neuroinflammatory responses that underlies the neuropathogenesis of HIV-1 infection its accompanying encephalitis (HIVE). These events ultimately lead to neuronal dysfunction and behavioral, cognitive and motor impairments in infected people. Copaxone (Cop-1) vaccination was previously shown to be neuroprotective by modulating microglial and T cell immunities. We determined whether Cop-1 could affect innate and adaptive immune responses relevant to HIV-1 infection of the nervous system and lead to neuroprotection.

Methods:  We used 2 murine models of HIVE to study Cop-1-induced innate and adaptive immune responses and their effects on glial inflammation and neurodegeneration. In the first, HIV-1-infected human monocyte-derived macrophages were injected into the basal ganglia of severe combined immunodeficient (SCID) mice devoid of functional T and B lymphocytes (SCID/HIVE). In the second, C57Bl/6 mice were injected intracranially with bone marrow-derived mouse macrophages infected with HIV-1/vesicular stomatitis virus pseudotypes (HIV/VSV-HIVE). Cop-1 vaccination was administered with or without Complete Fruend’s Adjuvant (CFA) and brain tissues subsequently examined immunohistochemically and by real-time polymerase chain reaction (PCR) for panel of inflammatory, glial, and neuronal markers and for birth of newborn neurons in the hippocampus.

Results:  Reductions in microglial- and astrocyte-induced inflammation in SCID/HIVE brain tissues of Cop-1-immunized mice was observed by immunohistology, with decreased expression of inducible nitric oxide synthase (iNOS) and up-regulation of anti-inflammatory cytokine (interleukin-10; IL-10) as assessed by real-time PCR. Neuronal integrity was significantly retained in Cop-1 SCID/HIVE animals. In HIV/VSV-HIVE mice, presence of adaptive immune response greatly enhanced Cop-1’s ability to control microphage-induced inflammation with reduced expression tumor necrosis factor-a (TNF-a), IL1-β, IL-6, and iNOS. Cop-1 adaptive immune response restored neuroregeneration in the hippocampus of HIVE animals.

Conclusions:  Cop-1 regulates both innate and adaptive immune responses in experimental models of HIVE and shows promise for treatment of human disease.