MECHANISMS FOR THE TRANSENDOTHELIAL MIGRATION OF HIV-1-INFECTED MONOCYTES INTO BRAIN

HIV-1 penetration of the brain is a pivotal event in the neuropathogen esis of AIDS-associated dementia. The establishment of productive vira l replication or up-regulation of adhesion molecule expression on brai n microvascular endothelial cells (BMVEC) could permit entry of HIV in to the central nervous system. To investigate the contribution of both , we inoculated primary human BMVEC with high titer macrophage-tropic HIV-1 or cocultured them with virus-infected monocytes. In both instan ces, BMVEC failed to demonstrate productive viral replication. Cell to cell contact between monocytes and microvascular endothelium resulted in E-selectin expression on BMVEC. BMVEC cocultured with LPS-activate d HIV-infected monocytes expressed even higher levels of E-selectin an d vascular cell adhesion molecule-1 (VCAM-1). Transwell assays support ed a role of soluble factors, from virus-infected monocytes, for the i nduction of adhesion molecules on BMVEC. To verify the in vivo relevan ce of these findings, levels of adhesion molecules were compared with these of proinflammatory cytokines and HIV-1 gene products in brain ti ssue of AIDS patients with or without encephalitis and HIV-seronegativ e controls. E-Selectin, and to a lesser degree VCAM-1, paralleled the levels of HIV-1 gene products and proinflammatory cytokines in brain t issue of subjects with encephalitis. Most importantly, an association between macrophage infiltration and increased endothelial cell adhesio n molecules was observed in encephalitic brains. Monocyte binding to e ncephalitic brain tissue was blocked with Abs to VCAM-1 and E-selectin . These data, taken together, suggest that HIV entry into brain is, in part, a consequence of the ability of virus-infected and immune-activ ated monocytes to induce adhesion molecules on brain endothelium.