HUMAN NEURAL XENOGRAFTS - PROGRESS IN DEVELOPING AN IN-VIVO MODEL TO STUDY HUMAN-IMMUNODEFICIENCY-VIRUS (HIV) AND HUMAN CYTOMEGALOVIRUS (HCMV) INFECTION

Human immunodeficiency virus type 1 (HIV-1) infection is highly specif ic for its human host. In order to study HIV-1 infection of the human nervous system, we have established a small animal model in which seco nd-trimester (11-17.5 weeks) human fetal brain or neural retina is tra nsplanted into the anterior chamber of the eye of immunosuppressed adu lt rats (Epstein et al., 1992; Cvetkovich et al., 1992), and more rece ntly in immunodeficient (SCID) mice. The human xenografts survive for many months, vascularize and form a blood-brain barrier. Immunohistoch emistry with PGP 9.5 identified neuronal cell bodies and neuritic proc esses. Electron microscopy revealed axonal growth cones and synaptic j unctions. Infection of these xenografts with cell-free HIV-1 proved di fficult, however co-engraftment with HIV-l-infected human monocytes re sulted in characteristic pathological changes, including the formation of syncytial giant cells, neuronal loss, and astroglial proliferation , supporting the hypothesis that these cells can mediate neurotoxicity . In other studies, xenografts of human fetal retinal tissue were read ily infected with cell-free human cytomegalovirus (HCMV) strain AD169. These grafts contained cells with intracytoplasmic and intranuclear i nclusions typical of HCMV infection. Productive infection within these grafts was demonstrated by the presence of immediate early, and late (capsid) HCMV antigens, by recovery of HCMV on human fibroblast cultur es, and by serial passage of virus to additional retinal xenografts (D iLoreto er al., 1994). The aim of these studies is to develop a small animal model to study direct and indirect effects of HIV-1 infection o n human neural tissues, and to study interactions between HIV-1 and ot her opportunistic pathogens such as HCMV. This model should prove usef ul in evaluating antiviral therapies.