HUMAN-IMMUNODEFICIENCY-VIRUS ENCEPHALITIS IN SCID MICE

The human immunodeficiency virus (HIV) is neuroinvasive and commonly c auses cognitive and motor deficits during the later stages of viral in fection (referred to as HIV dementia). The mechanism(s) for disease re volves around secretory products produced from immune-activated brain macrophages/microglia, Recently, we developed an animal model system f or HIV dementia that contains xenografts of HIV-1-infected cells inocu lated into brains of mice with severe combined immunodeficiency (SCID) , This animal system runs used to quantitatively evaluate HIV-induced neuropathology. Xenografts of HIV-1-infected human monocytes (placed i nto the putamen and cortex of SCID mice) remained viable for 5 weeks. HIV-1 p24 antigen expression in mouse brain was persistent. Progressiv e inflammatory responses (including astrogliosis and cytokine producti on), which began at 3 days, peaked at day 12, The range of astrocyte p roliferative reactions exceeded the inoculation site by >1000 mu m, Br ains with virus-infected monocytes showed a greater than or equal to 1 .6-fold increase in glial fibrillary acidic protein (staining distribu tion and intensity) as compared with similarly inoculated brains with uninfected control monocytes. These findings paralleled the accumulati on and activation of murine microglia (increased branching of cell pro cesses, formation of microglial nodules, interleukin (IL)-1 beta and I L-6 expression). An inflammatory reaction of human monocytes (as defin ed by HLA-DR, IL-1 beta, IL-6, and tumor necrosis factor-alpha express ion) and neuronal injury (apoptosis) also developed after virus-infect ed monocyte xenograft placement into mouse brain tissue. These data, t aken together, demonstrate that this SCID mouse model of HIV-1 neuropa thogenesis can reproduce key aspects of disease (virus-infected macrop hages, astrocytosis, microglial activation, and neuronal damage), This model may serve as an important means for therapeutic development dir ected toward improving mental function in HIV-infected subjects with c ognitive and motor dysfunction.