Human immunodeficiency virus (HIV) penetrates into the central nervous system (CNS) and leads to particularly rapid disease progression in children suggesting heightened viral penetration and pathogenic interactions in the immature brain. While antiretroviral therapies have been effective in reducing HIV infection in newborns, there are many important unresolved issues. Can exposure of the brain prior to antiretrovirals establish a latent reservoir in the brain? What is the relative penetration and distribution of virus in the neonatal brain? What is the cytokine and chemokine response of neonatal brain to HIV? Is chronic exposure to antiretroviral drugs toxic to the developing brain? Because early interactions of the virus with brain probably set the stage for subsequent disease progression, early direct intervention in conjunction with antiretrovirals is likely to be important for effective treatment of the neurological and behavioral complications of HIV infection. However, the development of effective therapeutic strategies requires more knowledge regarding the dissemination of virus in the brain, establishment and control of local viral reservoirs, clearance of virus from the brain and the mechanisms of pathogenesis. We will use feline immunodeficiency virus (FIV) as an animal model of HIV-induced CNS disease to examine virus penetration and cytokine and chemokine expression in the immature cat brain by quantitative RT-PCR. Cytotoxicity assays of CSF will be used to evaluate the production of toxic factors in cats infected with FIV and cats treated systemically with zidovudine. After systemic virus is suppressed in vivo with antiretroviral treatment, we will: 1). Evaluate virus transfer from the brain to the systemic circulation upon removal of anti retrovirrals, 2). Measure the stability of the brain viral reservoir and 3). Determine if neurological disease progresses in the absence of a systemic viremia. It is anticipated that these studies will clarify some of the early interactions of lentiviruses with neonatal brain and reveal possible therapeutic strategies to reduce CNS infection and pathogenesis.