Background:  The human immunodeficiency virus type 1 (HIV-1) Tat protein, a potent transactivator of viral and cellular genes, has been proposed as a key agent in the pathogenesis of acquired immune deficiency syndrome (AIDS)-related disorders, including HIV-1-associated dementia.  HIV-1 Tat protein is neurotoxic both in vivo and in vitro.  We have shown that Tat protein is taken up into neurons via low-density lipoprotein receptor related protein (LRP)-mediated endocytic pathway and then translocated into neurons in its biologically active form, and as a result, causes extracellular accumulation of LRP physiological ligands, such as a₂-macroglobulin, apolipoprotein E4, amyloid precursor protein, and b-amyloid peptide.  We hypothesize that such alterations in metabolic balance of LRP ligands, as well as a secondary genetic event triggered by nuclear Tat protein, ultimately contribute to HIV-associated dementia in AIDS patients. 

Methods:  A doxycycline-regulated, astrocyte glial fibrillary acidic protein (GFAP) promoter-specific HIV-1 Tat transgenic mouse model was developed.  Tat expression was examined in relation to GFAP promoter specificity, doxycycline inducibility, brain development, metabolism of LRP ligands, and neuron apoptosis.  Experimental methods included transgenic technique, genomic DNA PCR, in situ immunofluorescence staining, ELISA, LTR-driven reporter CAT reporter gene assay, RT-PCR, and TUNNEL staining. 

Results:  Tat protein was exclusively expressed in astrocytes in the brain of Tat transgenic mice, and the expression was regulated by doxycycline.  Tat expression resulted in astrocytosis, extracellular accumulation of LRP ligands, and neuron apoptosis.  Significantly increased numbers of CD8-, CD14-, and CD68-positive staining cells were also noted in the brain of Tat-expressing Tat transgenic mice.  Furthermore, Tat-expressing mice exhibited growth failure, cognitive impairment, stillborn pregnancy, and early death.

Conclusions: These results show that HIV-1 Tat expression in the absence of HIV-1 infection is capable of causing neuropathologies reminiscent of those noted in the brain of AIDS patients, further supporting the notion that Tat protein plays a key role in HIV-associated neuropathogenesis.  In addition, these results also suggest that improper immune activation by infiltrating monocyte/macrophages and T lymphocytes resulting from Tat expression may be one of the underlying mechanisms for Tat-induced neurotoxicity.  This model will help define molecular mechanisms of Tat neurotoxicity, as well as therapeutic strategies aimed at HIV-brain interaction.