TNF-ALPHA OPENS A PARACELLULAR ROUTE FOR HIV-1 INVASION ACROSS THE BLOOD-BRAIN-BARRIER

Background: HIV-1 invades the central nervous system early after infec tion when macrophage infiltration of the brain is low but myelin pallo r is suggestive of blood-brain-barrier damage. High-level plasma virem ia is a likely source of brain infection. To understand the invasion r oute, we investigated virus penetration across in vitro models with co ntrasting paracellular permeability subjected to TNF-alpha. Materials and Methods: Blood-brain-barrier models constructed with human brain m icrovascular endothelial cells, fetal astrocytes, and collagen I or fi bronectin matrix responded in a dose-related fashion to cytokines and ligands modulating paracellular permeability and cell migration. virus penetration was measured by infectious and quantitative HIV-1 RNA ass ays. Barrier permeability was determined using inulin or dextran. Resu lts: Cell-free HIV-1 was retained by the blood-brain barrier with clos e to 100% efficiency. TNF-alpha increased virus penetration by a parac ellular route in a dose-dependent manner proportionately to basal-perm eability. Brain endothelial cells were the main barrier to HIV-1. HIV- 1 with monocytes attracted monocyte migration into the brain chamber. Conclusions: Early after the infection, the blood-brain barrier protec ts the brain from HIV-1. Immune mediators, such as TNF-alpha, open a p aracellular route for the virus into the brain. The virus and viral pr oteins stimulate brain microglia and macrophages to attract monocytes into the brain. infiltrating macrophages cause pro progression of HIV- 1 encephalitis.