Cryptococcus neoformans infection has significantly increased recently, particularly in AIDS patients and immunocompromised individuals. C neoformans has a predilection to the brain, resulting in devastating meningoencephalitis. We have previously shown the invasion of C neoformans into the human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier. Here, we demonstrated that C. neoformans invasion of HBMEC was enhanced by HIV-1 gp41 protein. Peptide mapping defined its functional domain around the disulfide-bond linkage of gp41 molecule (a.a. 579-611). Recombinant protein gp41-190 (a.a. 550-639) can also enhance the binding activity. The enhancement of C neoformans binding to HBMEC is a strain-independent manner, suggesting that gp41 ectodomain peptide exerts its function directly on HBMEC. Importantly, the enhancement could be observed in mouse animal model. Our results Suggest that HIV-1 gp41 ectodomain and C. neoformans may follow a similar invasion mechanism, possibly actin reorganization and/or membrane activation, during pathogen infections oil HBMEC. (c) 2007 Elsevier Inc. All rights reserved.