HUMAN-IMMUNODEFICIENCY-VIRUS NEUROTROPISM - AN ANALYSIS OF VIRAL REPLICATION AND CYTOPATHICITY FOR DIVERGENT STRAINS IN MONOCYTES AND MICROGLIA

Productive replication of human immunodeficiency virus type 1 (HIV-1) in brain macrophages and microglia is a critical component of viral ne uropathogenesis. However, how virus-macrophage interactions lead to ne urological disease remains incompletely understood. Possibly, a differ ential ability of virus to replicate in brain tissue macrophages versu s macrophages in other tissues underlies HIV-1 neurovirulence. To thes e ends, we established systems for the isolation and propagation of pu re populations of human microglia and then analyzed the viral life cyc les of divergent HIV-1 strains in these cells and in cultured monocyte s by using identical viral inocula and indicator systems. The HIV-1 is olates included those isolated from bleed, lung tissue, cerebrospinal fluids (CSF), and brain tissues of infected subjects: HIV-1(ADA) and H IV-1(89.6) (from peripheral blood mononuclear cells), HIV-1(DJV) and H IV-1(JR-FL) (from brain tissue), HIV-1(SF162) (from CSF), and HIV-1(BA L) (from lung tissue). The synthesis of viral nucleic acids and viral mRNA, cytopathicity, and release of progeny virions were assessed. A s ignificant heterogeneity among macrophage-tropic isolates for infectio n of monocytes and microglia was demonstrated. Importantly, a complete analysis of the viral life cycle revealed no preferential differences in the abilities of the HIV-1 strains tested to replicate in microgli a and/or monocytes. Macrophage tropism likely dictates the abilities o f HIV-1 to invade, replicate, and incite disease within its microglial target cells.