Glial Cytokines as Neuropathogenic Factors in HIV InfectionPathogenic Similarities to Alzheimer's Disease

摘要

The mechanisms by which human immunodeficiency virus (HIV) infection provokes progressive neurodegeneration and dementia in acquired immunodeficiency syndrome (AIDS) remain obscure. In HIV-infected (HIV+) individuals, we found that the brain cells preferentially infected by HIV,viz. the microglia, were abundant, activated, and intensely immunopositive for interleukin-1 alpha (IL-lalpha;), an immune response-generated cytokine that increases the synthesis and processing of beta;-amyloid precursor proteins (beta;-APP) and promotes proliferation and activation of astroglia. We also found an increase in the number of activated astroglia expressing elevated levels of S100beta; a cytokine that increases intraneuronal calcium levels and promotes excessive growth of neuronal processes (neurites). These glial changes were accompanied by increased expression of 4bT-APP immunoreaction product in neurons and overgrown (dystrophic) neurites. In addition, some neurons contained monoclonal antibodyTau-2 immunopositive, neurofibrillary tangle-like structures. Our findings provide evidence that glial activation with increased expression of IL-1alpha; and S100beta; may be important in the neuropathogenesis of AIDS dementia. We propose that HIV infection promotes excessive microglial IL-1alpha; expression with consequent astrogliosis and increased expression of S100beta;. Overexpression of these two cytokines may then be involved in AIDS neuropathogenesis by inducing gliosis, growth of dystrophic neurites, and calcium-mediated neuronal cell loss in AIDS.