Encephalopathy is a common and serious manifestation in HIV-1 infected patients. HIV-1 enters into the CNS early after initial exposure but the underlying pathogenesis remains unclear. he current consensus is that HIV-1 enters into the CNS via HIV infected monocyte/macrophages, thereby crossing the endothelium of the blood brain barrier (BBB). Alcohol (ethanol) is commonly used and or abused in AIDS patients, but epidemiological studies show conflicting evidence whether alcohol affects the disease progression of AIDS. Many studies showed a detrimental effect of alcohol on a variety of cell types. However, cardiovascular studies indicated that alcohol could have beneficial effects as well but its effects on the brain microvascular endothelial cells (BMEC), which comprise the functional site of the BBS is unknown. We hypothesize that alcohol could alter the barrier properties of the BBB and thereby leading to increased transmigration of (HIV-1) infected rnonocytes across the BBB. Alcohol may also act in concert with HIV-1 proteins (gpl 20, Tat) and/or cytokines, present in the circulation of HIV-1 infected patients, and the detrimental effect of alcohol on HIV-1 pathogenesis could be exacerbated. We have previously developed an in-vitro model of the human BBB and showed that HIV-1 proteins (gpl2O and Tat) are able to activate BMEC, thereby increasing ICAM-1, VCAM-1 (CAM) expression, BMEC monolayer permeability and monocyte transmigration. Our preliminary experiments indicate that alcohol may exacerbate the activation of brain endothelium by HIV-1 proteins. In this study, we propose to investigate the potential of alcohol alone or in concert with HIV-1 proteins, to activate human BMEC, e.g. CAM expression, permeability / transendothelial electrical resistance, thereby concomitantly leading to increased transmigration of HIV-1 infected monocytes. The result of this study will delineate the effects of alcohol on the human BBB endothelium, indicate the implications for BBB barrier properties and the progression of the pathogenesis of HIV-1 encephalopathy.
| Shiu, Carlum; Barbier, Elisabeth; Cello, Francescopaolo Di et al. (2007) HIV-1 gp120 as well as alcohol affect blood-brain barrier permeability and stress fiber formation: involvement of reactive oxygen species. Alcohol Clin Exp Res 31:130-7 |
