The human immunodeficiency virus (HIV) encephalitis and its clinical counterpart, AIDS dementia, are frequent in patients with the acquired immunodeficiency syndrome (AIDS) and are important causes of neurological morbidity in this illness. The virus enters the cerebrospinal fluid (CSF) during the initial stage of systemic infection, but actual brain infection is rare or absent prior to the development of AIDS. The route(s) whereby HIV enters the brain and the time and site at which this occurs remain somewhat controversial or are not known. Recent studies in our laboratory have shown that the blood-brain barrier (BBB) is permeable in brains of AIDS patients and that the choroid plexus (CPx) often is infected by HIV. Both of these findings may be important in the neuropathogenesis of HIV encephalitis. This application will examine the following hypotheses: 1. that HIV infects the CPx during the early stages of systemic infection and resides here during the period of clinical latency and 2. that the enhanced vascular permeability in the brain is responsible for, or enhances, the development of HIVE. The proposed experiments will explore the relationship between the enhanced vascular permeability and the CPx changes with each other and with the development of HIVE; the phenotypic and genotypic characteristics of virus in CPx, brain and spleen to determine whether CPx infection is a prerequisite for the subsequent development of HIVE; the effects of the BBB in facilitating the entry into the brain of circulating immune cells, including those infected with HIV; and the potential relevance of circulating viral proteins in mediating the BBB and CPx changes in AIDS. The proposed studies will be carried out in post-mortem brains from HIV- infected asymptomatic cases and from AIDS cases with normal brains or with HIVE, using techniques of immunocytochemistry, in situ hybridization and molecular biology. In addition, animal models of circulating HIV proteins will be used to investigate mechanisms of, and abnormalities related to, the enhanced vascular permeability in AIDS and immunological and functional alterations in the CPx.
