NEURONAL DEATH INDUCED BY BRAIN-DERIVED HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENVELOPE GENES DIFFERS BETWEEN DEMENTED AND NONDEMENTED AIDS PATIENTS

Human immunodeficiency virus type 1 (HIV-1) infection of the brain res ults in viral replication primarily in macrophages and microglia. Desp ite frequent detection of viral genome and proteins in the brains of A IDS patients with and without HIV dementia, only 20% of AIDS patients become demented. To investigate the role of viral envelope gene variat ion in the occurrence of dementia, we examined regions of variability in the viral envelope gene isolated from brains of AIDS patients. Brai n-derived HIV-1 V1-V2 envelope sequences from seven demented and six n ondemented AIDS patients displayed significant sequence differences bt tween clinical groups, and by phylogenetic analysis, sequences from t he demented group showed clustering. Infectious recombinant viruses co ntaining brain derived V3 sequences from both clinical groups were mac rophagetropic, and viruses containing brain-derived V1, V2, and V3 seq uences from both clinical groups spread efficiently in macrophages. In an indirect in vitro neurotoxicity assay using supernatant fluid from HIV-1-infected macrophages, recombinant viruses from demented patient s induced greater neuronal death than viruses from nondemented patient s. Thus, the HIV-1 envelope diversity observed in these patient groups appeared to influence the release of neurotoxic molecules from macrop hages and might account in part for the variability in occurrence of d ementia in AIDS patients.