Molecular pathway involved in HIV-1-induced CNS pathology: role of viral regulatory protein, Tat

The broad range of histological lesions associated with HIV-1 are somewhat subtle relative to the clinical manifestations that occur as a result of HI V infection. Although it is clear that HIV has a causative role ll CNS dise ase, dementia appears to be a consequence of the infiltration of inflammato ry cells and cytokine dysregulation rather than the amount of virus ll CNS, The HIV transregulatory protein Tat plays an important intracellular as we ll as extracellular role ll the dysregulation of cytokines. The cytokines a nd possibly chemokines that are induced by Tat modify the action of astrocy tes such that the survival of neurons is compromised. Pathogenetic alterati on induced by Tat involves a series of interactions between circulating mon ocyte/macrophages, endothelial cells, and astrocytes. Cytokine dysregulatio n induced by viral infection and extracellular Tat leads to alterations in expression of adhesion molecules and promotes migration of non-infected inf lammatory cells into the CNS compartment. We demonstrate here that recombin ant HIV-1 Tat protein introduced by stereotaxic injection into mouse brain call induce pathologically relevant alterations including macrophage invasi on as well as astrocytosis, The mechanism of destruction of the CNS by Tat appears to involve autocrine and paracrine pathways that depend not only on Tat, but cytokine and. chemokine signaling pathways that are altered by vi ral infection. in this review, we discuss various pathogenic effects of Tat in brain cells and provide experimental evidence for an increased TNF-alph a. level in CSF in mice injected intracerebrally with Tat protein.