The long term goal of this project is to understand the mechanism of human immunodeficiency (HIV)-induced central nervous system (CNS) disease in AIDS. AIDS dementia complex (ADC) is an important neurological syndrome occurring in approximately 10-25 percent of HIV-infected individuals. Even with the success of anti-HIV triple drug therapy in eradicating virus from the circulatory system, recent evidence has indicated that the brain is still a major reservoir of virus. Although ADC has been the subject of intense study by many groups, the cause(s) of the syndrome are unknown. The overall aim of this project is to characterize the role of HIV infection of human brain capillary endothelial (BMVEC) cells in the pathogenesis of AIDS dementia. MVEC are naturally infected by HIV in vivo in both the brain and bone marrow of humans as well as SIV-infected macaques. The investigators hypothesize that HIV infection of BMVEC contributes to AIDS neuropathogenesis by acting as a reservoir of viral amplification which facilitates transfer of virus into the brain parenchyma. In addition, viral infection of BMVEC may perturb formation of tight junctions (TJ) in the BBB with neurotoxic consequences. Over the past funding period, the investigators have identified the HIV gp120 sequences which mediate HIV entry into BMVEC as well as the cellular adhesion molecules which are upregulated and may alter the trafficking of peripheral blood mononuclear cells into the brain parenchyma. They have also obtained preliminary evidence that HIV inhibits the formation of TJ which are essential for BBB function. Finally, they have established an in vitro BBB (DIV BBB) which demonstrates the same functional and physiological characteristics of the BBB in vivo such as high electrical resistance and selective transport of ions from the luminal to the abluminal compartment. In the current proposal, they plan to extend these observations to understand mechanisms of HIV neuroinvasion and pathogenesis. In the first specific aim, they will identify mechanisms which mediate intracellular trafficking of virus to the basolateral surface which may determine the ability of the virus to cross the BBB. In these experiments, they will introduce into the cytoplasmic tail of gp 41, which has been implicated in the trafficking of glycoprotein to the basolateral surface, to test in polarized BMVEC. In the second specific aim, they will identify the HIV gene(s) that dramatically inhibit the formation of TJ utilizing viral vectors expressing individual and combinations of viral genes. In the last specific aim, they will utilize the DIV BBB to examine the ability of HIV to perturb barrier function, including: decrease in electrical resistance, permeability to sucrose and stereospecific uptake of amino acids. This model will also be used to examine the ability of trafficking mutants to cross the DIV BBB as well as the effect of HIV genes which inhibit TJ formation. The successful completion of this project will identify mechanisms of HIV entry into the brain parenchyma as well as viral perturbation of BBB. Experiments proposed in this project aim to establish the usefulness of the DIV BBB as a model for analyzing the function of this organ during disease processes.
| Strelow, Lisa; Janigro, Damir; Nelson, Jay A (2002) Persistent SIV infection of a blood-brain barrier model. J Neurovirol 8:270-80 |
| Moses, A V; Williams, S E; Strussenberg, J G et al. (1997) HIV-1 induction of CD40 on endothelial cells promotes the outgrowth of AIDS-associated B-cell lymphomas. Nat Med 3:1242-9 |
| Moses, A V; Williams, S; Heneveld, M L et al. (1996) Human immunodeficiency virus infection of bone marrow endothelium reduces induction of stromal hematopoietic growth factors. Blood 87:919-25 |
