INFECTION OF PRIMARY HUMAN MICROGLIA AND MONOCYTE-DERIVED MACROPHAGESWITH HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ISOLATES - EVIDENCE OF DIFFERENTIAL TROPISM

To ascertain whether viruses present at the time of primary viremia ca n infect the central nervous system and to determine if microglial tro pism is distinct from tropism for monocyte-derived macrophages (MDM), 27 human immunodeficiency virus type 1 (HIV 1) isolates obtained from acutely infected individuals, as well as laboratory strains, were assa yed for their ability to replicate in primary adult microglial culture s and in MDM. Most of the isolates replicated equally well in both mic roglia and MDM, but several isolates replicated preferentially in one of the two cell types, differing by as much as 40-fold in p24(gag) pro duction. This indicated that while MDM and microglial tropism overlap, a subset of isolates is particularly tropic for one of the two cell t ypes. One isolate was further adapted to microglia by 15 sequential pa ssages, raising the peak p24 concentration produced by 1,000-fold. In addition, the passaged virus induced marked cytopathologic changes (va cuolization and syncytium formation) in infected microglial cultures. Sequence comparison of the V3 loop of unpassaged and multiply passaged virus revealed amino acid changes shown to be associated with isolate s from patients with HIV dementia. Our data support the hypothesis tha t HIV-1 infection can be established in the central nervous system by viruses present early in HIV infection, that some of these viruses ale particularly tropic for microglia, and that adaptation in this cell t ype can result in the selection of a pool of predominantly microglia-t ropic (neurotropic) viruses.